TW200817319A - Sulfonamide compound or salt thereof - Google Patents
Sulfonamide compound or salt thereof Download PDFInfo
- Publication number
- TW200817319A TW200817319A TW096129052A TW96129052A TW200817319A TW 200817319 A TW200817319 A TW 200817319A TW 096129052 A TW096129052 A TW 096129052A TW 96129052 A TW96129052 A TW 96129052A TW 200817319 A TW200817319 A TW 200817319A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- lower alkyl
- methyl
- ring
- chloro
- Prior art date
Links
- -1 Sulfonamide compound Chemical class 0.000 title claims abstract description 51
- 150000003839 salts Chemical class 0.000 title claims abstract description 47
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 101150058615 Ptger1 gene Proteins 0.000 claims abstract description 39
- 206010071289 Lower urinary tract symptoms Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 84
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 57
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 37
- 238000004519 manufacturing process Methods 0.000 claims description 36
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 239000005711 Benzoic acid Substances 0.000 claims description 30
- 235000010233 benzoic acid Nutrition 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000004471 Glycine Substances 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229940044551 receptor antagonist Drugs 0.000 claims description 19
- 239000002464 receptor antagonist Substances 0.000 claims description 19
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 16
- 210000004907 gland Anatomy 0.000 claims description 16
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical group COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 11
- 206010020880 Hypertrophy Diseases 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 9
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 125000003147 glycosyl group Chemical group 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 201000003146 cystitis Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 235000019260 propionic acid Nutrition 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 8
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 7
- 229930016911 cinnamic acid Natural products 0.000 claims description 7
- 235000013985 cinnamic acid Nutrition 0.000 claims description 7
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 7
- 206010049576 Bladder neck sclerosis Diseases 0.000 claims description 5
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005577 anthracene group Chemical group 0.000 claims description 4
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 208000020629 overactive bladder Diseases 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 229940114081 cinnamate Drugs 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims 2
- DRMOCHGNKTXIBF-UHFFFAOYSA-N 2-(2-methoxyanilino)acetic acid Chemical compound COC1=CC=CC=C1NCC(O)=O DRMOCHGNKTXIBF-UHFFFAOYSA-N 0.000 claims 1
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 claims 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 claims 1
- 239000005639 Lauric acid Substances 0.000 claims 1
- LCPUWQLULVXROY-RHYQMDGZSA-N Met-Lys-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LCPUWQLULVXROY-RHYQMDGZSA-N 0.000 claims 1
- LXUJDHOKVUYHRC-KKUMJFAQSA-N Phe-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N LXUJDHOKVUYHRC-KKUMJFAQSA-N 0.000 claims 1
- 241000700161 Rattus rattus Species 0.000 claims 1
- LJSZPMSUYKKKCP-UBHSHLNASA-N Val-Phe-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 LJSZPMSUYKKKCP-UBHSHLNASA-N 0.000 claims 1
- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical group COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims 1
- 230000003042 antagnostic effect Effects 0.000 abstract description 5
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 150000003456 sulfonamides Chemical class 0.000 abstract description 2
- 150000001408 amides Chemical group 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 157
- 235000019439 ethyl acetate Nutrition 0.000 description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 55
- 230000002829 reductive effect Effects 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000002904 solvent Substances 0.000 description 42
- 239000000203 mixture Substances 0.000 description 40
- 239000000460 chlorine Substances 0.000 description 38
- 101150117004 atg18 gene Proteins 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 125000004093 cyano group Chemical group *C#N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 230000002485 urinary effect Effects 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- 208000024891 symptom Diseases 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 229960002986 dinoprostone Drugs 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 235000011054 acetic acid Nutrition 0.000 description 10
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 230000008485 antagonism Effects 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 229940126585 therapeutic drug Drugs 0.000 description 7
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 6
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 6
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 240000006394 Sorghum bicolor Species 0.000 description 6
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 6
- 230000027939 micturition Effects 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 150000003536 tetrazoles Chemical class 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 101100241173 Caenorhabditis elegans dat-1 gene Proteins 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000001925 cycloalkenes Chemical group 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000000762 glandular Effects 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229940095102 methyl benzoate Drugs 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000006277 sulfonation reaction Methods 0.000 description 3
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 210000001635 urinary tract Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LJHFIVQEAFAURQ-ZPUQHVIOSA-N (NE)-N-[(2E)-2-hydroxyiminoethylidene]hydroxylamine Chemical compound O\N=C\C=N\O LJHFIVQEAFAURQ-ZPUQHVIOSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 2
- OJHWPOJTJKJBLA-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-benzimidazole Chemical compound C1C=CC=C2NCNC21 OJHWPOJTJKJBLA-UHFFFAOYSA-N 0.000 description 2
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 2
- SLDXYMDZMUHQHX-UHFFFAOYSA-N 3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]methyl]-4-fluorobenzoic acid Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)CC1=CC(C(O)=O)=CC=C1F SLDXYMDZMUHQHX-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- YQDGQEKUTLYWJU-UHFFFAOYSA-N 5,6,7,8-tetrahydroquinoline Chemical compound C1=CC=C2CCCCC2=N1 YQDGQEKUTLYWJU-UHFFFAOYSA-N 0.000 description 2
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 2
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- WKQSXJMUQXYURR-UHFFFAOYSA-N ethyl 4-fluoro-3-methylbenzoate Chemical compound CCOC(=O)C1=CC=C(F)C(C)=C1 WKQSXJMUQXYURR-UHFFFAOYSA-N 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 235000011147 magnesium chloride Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000000422 nocturnal effect Effects 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229960003540 oxyquinoline Drugs 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 230000035922 thirst Effects 0.000 description 2
- 238000003971 tillage Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- KCGZGJOBKAXVSU-UHFFFAOYSA-N (4-iodophenyl)methanamine Chemical compound NCC1=CC=C(I)C=C1 KCGZGJOBKAXVSU-UHFFFAOYSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- PUNXVEAWLAVABA-UHFFFAOYSA-N 1,2,3,4-tetrahydroanthracene;1,2,5,6-tetrahydroanthracene Chemical compound C1=CC=C2C=C(CCCC3)C3=CC2=C1.C1=CCCC2=C1C=C1CCC=CC1=C2 PUNXVEAWLAVABA-UHFFFAOYSA-N 0.000 description 1
- HHRXXMPYHLOPAO-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline;1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1.C1=CC=C2CNCCC2=C1 HHRXXMPYHLOPAO-UHFFFAOYSA-N 0.000 description 1
- MUHCEAIVGKVBHE-UHFFFAOYSA-N 1,2,5-thiadiazol-3-one Chemical compound OC=1C=NSN=1 MUHCEAIVGKVBHE-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- FUOSTELFLYZQCW-UHFFFAOYSA-N 1,2-oxazol-3-one Chemical compound OC=1C=CON=1 FUOSTELFLYZQCW-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical group NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- IGFLLQNIGPBMTN-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]piperidin-2-one Chemical compound C1=CC(CN)=CC=C1N1C(=O)CCCC1 IGFLLQNIGPBMTN-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SBPIDKODQVLBGV-UHFFFAOYSA-N 1h-imidazole;pyridine Chemical compound C1=CNC=N1.C1=CC=NC=C1 SBPIDKODQVLBGV-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 1
- XLGVHAQDCFITCH-UHFFFAOYSA-N 2,3-dihydroxypropanamide Chemical compound NC(=O)C(O)CO XLGVHAQDCFITCH-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- URWUMYHKFHYQBO-UHFFFAOYSA-N 2-(3-chloro-2-methyl-n-(4-methylphenyl)sulfonylanilino)-n-[(3-cyanophenyl)methyl]acetamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N(C=1C(=C(Cl)C=CC=1)C)CC(=O)NCC1=CC=CC(C#N)=C1 URWUMYHKFHYQBO-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- GHUHVSDGEXCCKY-UHFFFAOYSA-N 2-bromo-n-[(4-methoxyphenyl)methyl]acetamide Chemical compound COC1=CC=C(CNC(=O)CBr)C=C1 GHUHVSDGEXCCKY-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- IGAVZWMNOPFOCW-UHFFFAOYSA-N 2h-1,2,4-thiadiazol-5-one Chemical compound O=C1NC=NS1 IGAVZWMNOPFOCW-UHFFFAOYSA-N 0.000 description 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- SGHBRHKBCLLVCI-UHFFFAOYSA-N 3-hydroxybenzonitrile Chemical compound OC1=CC=CC(C#N)=C1 SGHBRHKBCLLVCI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- STABAPSYCQFWOK-UHFFFAOYSA-N 4-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=C(Cl)C=C1 STABAPSYCQFWOK-UHFFFAOYSA-N 0.000 description 1
- VOCCEVKUXUIHOI-UHFFFAOYSA-N 4-fluoro-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1F VOCCEVKUXUIHOI-UHFFFAOYSA-N 0.000 description 1
- DIRCLGLKRZLKHG-UHFFFAOYSA-N 4-hydroxybenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(O)C=C1 DIRCLGLKRZLKHG-UHFFFAOYSA-N 0.000 description 1
- HTMGQIXFZMZZKD-UHFFFAOYSA-N 5,6,7,8-tetrahydroisoquinoline Chemical compound N1=CC=C2CCCCC2=C1 HTMGQIXFZMZZKD-UHFFFAOYSA-N 0.000 description 1
- ZXRAYQMGMLKZGL-UHFFFAOYSA-N 5-(aminomethyl)-1-methylpyrrole-2-carboxylic acid Chemical compound CN1C(CN)=CC=C1C(O)=O ZXRAYQMGMLKZGL-UHFFFAOYSA-N 0.000 description 1
- ADLJPAZQSGCYCX-UHFFFAOYSA-N 5-(chloromethyl)thiophene-3-carboxylic acid Chemical compound OC(=O)C1=CSC(CCl)=C1 ADLJPAZQSGCYCX-UHFFFAOYSA-N 0.000 description 1
- DXKZEUUVPWJJCX-UHFFFAOYSA-N 9h-fluorene;hydrochloride Chemical compound Cl.C1=CC=C2CC3=CC=CC=C3C2=C1 DXKZEUUVPWJJCX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 1
- 101001134782 Arabidopsis thaliana Precursor of CEP4 Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005063 Bladder pain Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- NQKBALGQCSCMGJ-UHFFFAOYSA-N C(C)OC(C)=O.C(C)OP(OCC)=O Chemical compound C(C)OC(C)=O.C(C)OP(OCC)=O NQKBALGQCSCMGJ-UHFFFAOYSA-N 0.000 description 1
- FUWXCBQJKGNLNU-UHFFFAOYSA-N C1=CC=CC=C1.O1C=NC=C1 Chemical compound C1=CC=CC=C1.O1C=NC=C1 FUWXCBQJKGNLNU-UHFFFAOYSA-N 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010011416 Croup infectious Diseases 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 1
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- 101100218335 Dictyostelium discoideum aurK gene Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- BVTJGGGYKAMDBN-UHFFFAOYSA-N Dioxetane Chemical group C1COO1 BVTJGGGYKAMDBN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KBEBGUQPQBELIU-CMDGGOBGSA-N Ethyl cinnamate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1 KBEBGUQPQBELIU-CMDGGOBGSA-N 0.000 description 1
- XZWYTXMRWQJBGX-VXBMVYAYSA-N FLAG peptide Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 XZWYTXMRWQJBGX-VXBMVYAYSA-N 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 206010061979 Genital pain Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000017278 Glutaredoxin Human genes 0.000 description 1
- 108050005205 Glutaredoxin Proteins 0.000 description 1
- FMAZQSYXRGRESX-UHFFFAOYSA-N Glycidamide Chemical compound NC(=O)C1CO1 FMAZQSYXRGRESX-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 244000147568 Laurus nobilis Species 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010027566 Micturition urgency Diseases 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010069645 Reduced bladder capacity Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- ZTMORTKTQUFTOF-UHFFFAOYSA-N S1C=NC=C1.C1(C=CC(C=C1)=O)=O Chemical compound S1C=NC=C1.C1(C=CC(C=C1)=O)=O ZTMORTKTQUFTOF-UHFFFAOYSA-N 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- 206010039757 Scrotal pain Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- XBDYBAVJXHJMNQ-UHFFFAOYSA-N Tetrahydroanthracene Natural products C1=CC=C2C=C(CCCC3)C3=CC2=C1 XBDYBAVJXHJMNQ-UHFFFAOYSA-N 0.000 description 1
- 208000026062 Tissue disease Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010046461 Urethral pain Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 108010006886 Vitrogen Proteins 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- GOEPRUGOSZYQMI-UHFFFAOYSA-N [Br].NN Chemical compound [Br].NN GOEPRUGOSZYQMI-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- RLQDALSZUFCRBX-UHFFFAOYSA-N bromoethane hydrobromide Chemical compound Br.CCBr RLQDALSZUFCRBX-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000010549 croup Diseases 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- GPMMYQITJVUZAT-UHFFFAOYSA-N cyclohex-2-ene-1,4-dione Chemical compound O=C1CCC(=O)C=C1 GPMMYQITJVUZAT-UHFFFAOYSA-N 0.000 description 1
- JVXNCJLLOUQYBF-UHFFFAOYSA-N cyclohex-4-ene-1,3-dione Chemical compound O=C1CC=CC(=O)C1 JVXNCJLLOUQYBF-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ISWSRQNCRDFATO-UHFFFAOYSA-N ethyl 2-(3-cyanophenoxy)acetate Chemical compound CCOC(=O)COC1=CC=CC(C#N)=C1 ISWSRQNCRDFATO-UHFFFAOYSA-N 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- ZMJLCDQAFPCHMK-UHFFFAOYSA-N ethyl 3-(bromomethyl)-4-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C(CBr)=C1 ZMJLCDQAFPCHMK-UHFFFAOYSA-N 0.000 description 1
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- YFJPIWIHHBIIRK-CQSZACIVSA-N methyl (2r)-2-[3-[[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]methyl]phenoxy]propanoate Chemical compound COC(=O)[C@@H](C)OC1=CC=CC(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=C1 YFJPIWIHHBIIRK-CQSZACIVSA-N 0.000 description 1
- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 1
- BEOUVMACJSPYHM-UHFFFAOYSA-N methyl 5-(hydroxymethyl)-1-methylpyrrole-2-carboxylate Chemical compound COC(=O)C1=CC=C(CO)N1C BEOUVMACJSPYHM-UHFFFAOYSA-N 0.000 description 1
- CWXHYNWAHPPMJH-UHFFFAOYSA-N methyl 5-(hydroxymethyl)thiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(CO)=C1 CWXHYNWAHPPMJH-UHFFFAOYSA-N 0.000 description 1
- QKSKGFBSJJNUCW-UHFFFAOYSA-N methyl 5-[(1,3-dioxoisoindol-2-yl)methyl]-1-methylpyrrole-2-carboxylate Chemical compound CN1C(C(=O)OC)=CC=C1CN1C(=O)C2=CC=CC=C2C1=O QKSKGFBSJJNUCW-UHFFFAOYSA-N 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- KFYLTOOSQRSNRF-UHFFFAOYSA-N n-(3-chloro-2-methylphenyl)-4-fluorobenzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1NS(=O)(=O)C1=CC=C(F)C=C1 KFYLTOOSQRSNRF-UHFFFAOYSA-N 0.000 description 1
- KPRWHOCOWVZODI-UHFFFAOYSA-N n-(3-chloro-2-methylphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=CC(Cl)=C1C KPRWHOCOWVZODI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- KAVSMINTEBGDTI-UHFFFAOYSA-N pyridine;thiophene Chemical compound C=1C=CSC=1.C1=CC=NC=C1 KAVSMINTEBGDTI-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- DDWJFSYHYPDQEL-UHFFFAOYSA-N pyrimidine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CN=CN=C1 DDWJFSYHYPDQEL-UHFFFAOYSA-N 0.000 description 1
- 150000004060 quinone imines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- PYBFOHHUUMLRKD-UHFFFAOYSA-M sodium ethyl acetate chloride hydrate Chemical compound [OH-].[Na+].Cl.C(C)(=O)OCC PYBFOHHUUMLRKD-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- IKACLGBUTCDQFA-UHFFFAOYSA-N sulfane;toluene;hydrochloride Chemical compound S.Cl.CC1=CC=CC=C1 IKACLGBUTCDQFA-UHFFFAOYSA-N 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000003202 urodynamic effect Effects 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/47—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
- C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Furan Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Description
200817319 九、發明說明 【發明所屬之技術領域】 本發明乃下部尿道症狀之治療藥有用之EP1受體拮抗 劑有關。又,本發明也有關做爲EP 1受體拮抗劑有用之磺 胺化合物或其製藥學上容許之鹽。 【先前技術】 過動膀胱爲導致下部尿道症狀之疾病之一種,其病狀 爲無論有無失禁始終訴諸急迫尿意感覺,一般伴有頻尿及 夜間頻尿(參照非專利文獻1 )。目前,其治療主要使用 抗膽汁素劑,也顯示肯定之治療績效。然而,也發現有口 渴、便秘、眼睛模糊等副作用之外,尙有閉尿之危險性, 據報告很難在前立腺肥大病患者或高齡者身上使用。另外 ,也已知使用抗膽汁素治療完全無效之病患者之存在。據 此,期待對於過動膀胱有新穎機制之藥劑之硏發。 前列腺素E2 ( PGE2 )乃以花生四烯酸爲前驅物質之體 內活性物質,已知介由G蛋白共軛型受體之EP1、EP2、 EP3及EP4之四種亞型影響體內機能調整。 已知膀胱內注入PGE2會導致人之強急迫尿意感覺及 減少膀胱容量(參照非專利文獻2 ),也已知膀胱內注入 PGE2會減少鼠之膀胱容量(參照非專利文獻3 ),暗示對 於下部尿道機能之pge2之影響之可能性。最近,據報告 對於脊髓受損模型鼠試驗動物投予EP 1受體拮抗劑,有益 於排尿機能之改善(參照非專利文獻4 ),另外,尿道狹 -5- 200817319 窄模型鼠之排尿機能異常可藉打倒EP 1受體而消失,以及 肪胱內注入P G E 2顯示排尿機能異常會宄進(參照專利文 獻1 ),可推測EP 1受體拮抗劑做爲下部尿道症狀之治療藥 必有其用途。 再加上’由EP 1受體拮抗劑之作用機制,可期待能回 避抗膽汁劑特有之副作用之外,對於抗膽汁劑治療無效之 病患者也能期待其藥效。又,本藥劑能期待其作用在知覺 神經而改善自覺症狀之效果。又,據報告在不降低脊髓受 損鼠之排尿效率下能改善病狀效果(參照非專利文獻5 ) ,因此,可望在前立腺肥大病患者或高齢者身上也能完全 投予使用。 又,PGE2伴隨炎症或組織障礙而在局部產生,可增 強炎症反應,同時也和發病、發熱有關已廣爲人知。最近 ,已知EP 1受體拮抗劑對於炎症性疼痛(參照非專利文獻6 )、術後疼痛(參照非專利文獻7 )、神經性疼痛(參照 非專利文獻8 )等各種疼痛模型動物之有效性,另外,也 有報告對於鹽酸誘致內臟疼痛有關EP 1受體拮抗劑投予之 臨床效果(參照非專利文獻9 )等。據此,可知EP 1受體拮 抗劑做爲各種疼痛之治療藥也有用途。 加之’已知EP 1受體拮抗劑具有抑制大腸黏膜異常腺 高及腸內異常突起之形成作用(參照專利文獻2 ),可知 EP 1受體拮抗劑做爲大腸癌、膀胱癌、前立腺癌等之治療 藥也有其用途。 具有EP 1受體拮抗活性之磺胺化合物,已有例如專利 200817319 文獻3及4所示化合物有關報告。 專利文獻3中揭示式(A )所示化合物 【化1】
R (式中,A及B各自獨立示C5〜15之碳環或5〜展 Z3示單鍵結合或Cl〜4伸烷基,Z4示S〇2或C0 ’ R示酿胺 結合,-Ο-Cl〜4伸烷基等。R4示(1)氫原子、(2)C1 〜8烷基、C2〜8烯基、C2〜8炔基、(3) 1個或2個<:0028 、CONZ9Z1Q、OZ8、C1〜4烷氧基所構成基選擇之基所取 代之C1〜6烷基、(4) C3〜7環烷基、(5)由苯基或C3 〜7環烷基取代之Cl〜4烷基、C2〜4烯基、C2〜4炔基, 又,Z8、Z9、Z1G各自獨立示氫原子或C1〜4烷基。其他符 號之意義可參照該公報)。 然而,本發明之有效成份之式(〗)所示化合物並無 具體揭示。 又,專利文獻4中揭示式(B )所示化合物。 200817319
(式中,R5示異丙基、異丁基、2—甲基一2 —丙烯基、環 丙基甲基、甲基、乙基、丙基、2 —丙烯基、或2-羥基一 2 -甲基丙基。其他符號之意義可參照該公報)。 然而,R5不具有醯胺構造,所以跟本發明之有效成份 之式(I )所示化合物之基本構造不相同。 又,例如專利文獻5〜8中也有磺胺化合物之報告。 專利文獻5中,揭示包括廣範圍之化合物之式(C )所 示化合物具有澱粉狀蛋白Θ蛋白質之產生阻礙作用,可提 供阿滋海馬病等之治療或預防用途。 【化3】 V 〇 式中符號之意義可參照該公報)。 然而,該化合物之EP1受體拮抗作用並無有關記載 -8- 200817319 也沒有本發明化合物(II)之具體的揭示。 又,專利文獻6中揭示包括廣範圍之化合物之式(D )所示化合物具有法呢索X受體(FXR )拮抗作用,對於 因爲膽固醇之異常所致疾病、肥胖、糖尿病等之治療有用 〇 【化4】 B1—L-A—L-B2 (D) (式中符號意義可參照該公報)。 然而,該化合物也無EP 1受體拮抗作用有關記載,也 無本發明化合物(II )之具體揭示。 又,專利文獻7中揭示式(E )所示化合物具有開胃鹼 受體拮抗作用,對於腫眠障礙、壓力相關障礙等之治療有
(式中符號之意義參照該公報)。 然而,該化合物也無EP 1受體拮抗作用有關之記載, 也無本發明化合物(II )之具體之揭示。 更於專利文獻8中揭示式(F)所示具有甘油二酯醯基 轉移酶(DGAT )阻礙作用,對於肥胖、高脂血症、糖尿 200817319 病等之治療或預防有用。 【化6】
(F) (式中符號之意義可參照該公報)° 然而,該化合物也無EP1受體掊抗作用有關之記載, 也沒有本發明化合物(Π )之具體之揭示。 又,4({[N— [(4—氟苯基)磺醯基]—N —(2 —甲 氧苯基)甘胺醯基]胺基}甲基)苯甲酸甲酯(Registry Number : 8 5 1 1 72 - 0 9 - 3 ;例如文獻名:Aur ora S creening
Library,訂購號碼:Kend-0 1 00022 )、具有阻斷澱粉狀 蛋白Θ蛋白質之產生作用的N2 — [(4 一氯苯基)磺醯基] —N2— (2,5—二氟苯基)—N— [4— (1,2,3- 噻二唑—4 一基)苯甲基]—D -丙胺醯胺(專利文獻5、實施例63 5 ) 亦爲人所知。 惟,完全無關於此等化合物的EP 1受體拮抗作用之報 告。 非專利文獻1 : Neurourology and Urodynamics, (英 國),2002年,第21卷,167〜78頁。 非專利文獻 2 : Urological Research,(美國),1990 年,第18卷,第5期,349〜52頁。 非專利文獻 3 : The Journal of Urology,(美國) -10- 200817319 1 995年6月,第153卷,第6期,2034-8頁。 非專利文獻4 :日本泌尿器科學會雜誌,2〇〇1年2月, 第92卷,第2期,3 04頁。 非專利文獻5 ·弟8 9屆日本泌尿器科學會大會預稿集 ,神戶,200 1 年,MP-3 05 ° 非專利文獻 6 : Anesthesiology,(美國),2002 年, 11月,第97卷,第5期,1 254〜62頁。 非專利文獻 7 : Anesthesia and Analgesia,(美國) ,2002年12月,第95卷,第6期,1 70 8〜12頁。 非專利文獻 8: Anesthesia and Analgesia,(美國) ,200 1年10月,第93卷,第4期,1012〜7頁。 非專利文獻 9: Gastroenterology,2003年 1月,第 124 卷,第1期,18〜25頁。 專利文獻1 :美國專利申請公開第2005/0020646號說 明書。 專利文獻2 :國際公開第00/06946 5號小冊子。 專利文獻3 :國際公開第9 8/02705 3號小冊子。 專利文獻4 :國際公開第02/072 5 64號小冊子。 專利文獻5 :國際公開第00/05 03 9 1號小冊子。 專利文獻6 :國際公開第02/02 0463號小冊子。 專利文獻7 :國際公開第04/03 3 4 1 8號小冊子。 專利文獻8 :曰本專利2005-206492號公報。 【發明內容】 -11 - 200817319 發明擬解決之課題 已有之下部尿道症狀之治療藥如同上述在藥效性、安 全性等皆難令人滿意,因此,急待有藥效性、安全性皆優 異之下部尿道症狀之治療藥之問世。 解決課題之方法 EP 1受體拮抗劑如同上述口渴、閉尿等副作用少,可 期待其成爲安全性高之下部尿道症狀之治療藥用途。因此 ,本發明硏究者以提供下部尿道症狀之治療上有用之化合 物爲目的,努力從事具有EP 1受體拮抗活性之化合物之硏 究,發現本發明之有效成份之式(I )所示化合物具有強 力的EP 1受體拮抗作用,終於完成了本發明。 即,本發明包括下列項目: [1]提供含有式(I)所示磺胺化合物或其製藥學上 容許之鹽爲有效成份之EP 1受體拮抗劑。 【化7】
[式中符號之意義如下: A環:苯環、環烷環、或芳香族雜環、 -12- 200817319 L 1 :單鍵結合、或低級伸烷基、 L2 :低級伸烷基、 R1〜R4 :可爲相同或不同構造,分SU示RQ、鹵素、鹵化低 級烷基、-〇RG、-〇-鹵化低級烷基、-S(0)n-低級烷基、、 CN、-N〇2、含氮雜環基、環烷基、-NH-CO-低級烷基、 -NH-CO-NCR。0)〗、-NH-CO-含氮雜環基、-CO2R0、 -C Ο N (R G ) 2、- C Ο -低級院基、-低級伸院基-〇 R。、-低級伸 烷基-C02V,亦可被取代之芳基,亦可被取代之雜芳_ ,-〇_亦可被取代之芳基,-0 -苯甲基,或-0-亦可被取代 之雜芳基。 或R1和R2,以及R3和R4係分別互相在苯環及鄰接A環 之碳原子上時,可跟所結合之環原子成爲一體形成5〜7節 環烯環、苯環或由選擇自下列G1群中之基所取代之雜環, G1群:低級烷基、酮基、-〇RG,-低級伸烷基-〇RG及 -C 0 -低級院基’ V:氫原子、或低級烷基、 :氫原子、或可爲-org取代之低級烷基、 η : 0、1 或 2、 R/ : R〇、 RB : 、-低級伸烷基-亦可被取代之芳基,低級伸烷基_ 亦可被取代之雜芳基,-低級伸烷基-0-亦可被取代之芳基 ,或-低級伸院基-〇 -亦可被取代之雜芳基, 或RA和RB跟其所結合之氮原子成爲一體形成含氮雜 環。以下皆相同]。 -13- 200817319 [2] 如同[Π項之EP1受體拮抗劑,其中,RA示氫原子 、RB示-低級伸烷基-亦可被取代之芳基,-低級伸烷基-亦 可被取代之雜芳基,-低級伸烷基-〇-亦可被取代之芳基, 或-低級伸烷基-〇-亦可被取代之雜芳基。 [3] 式[II]所示磺胺化合物或其製藥學上容許之鹽。 【化8】 R1
Rj& 〇 R5 R6
r2-^X R3v [式中之符號之意義如下: A環:苯環、環烷環、或芳香族雜環、 L 1 :單鍵結合、或低級伸烷基、 L2 :低級伸烷基、 R1〜R4 :可爲相同或不同構造,示RG、鹵素、鹵化低級垸 基、-ORG、鹵化低級烷基、-S(0)n-低級烷基、-CN、 -N02、含氮雜環基、環烷基、-NH-CO-低級烷基、 -NH-C0-N(Rgg)2、-NH_C0_含氮雜環基、-co2r0、 -CONiR^h、-Co-低級烷基、-低級伸烷基-0Rg、-低級伸 烷基-C〇2RG,亦可被取代之芳基,亦可被取代之雜芳基, -〇-亦可被取代之芳基,-〇-苯甲基,或-0-亦可被取代之 雜芳基、 -14- 200817319 或R1和R2以及R3和R4,分別互相在苯環以及鄰接於A 環之碳原子上時,可和所結合之環原子成爲一體,形成5 〜7節環烯環、苯環、或以選擇自下列G1群之基取代之雜 環、 G1群:低級烷基、氧代基、-〇RG、-低級伸烷基-OM,以 及 -CO-低級烷基、 V :氫原子、或低級烷基、 :氫原子、或可被-OW所取代之低級烷基、 η : 0、1 或 2、 L3 :低級伸烷基、 X :單鍵結合、或-0 -、 Β環:苯環、或芳香族雜環、 R5及R6 :可爲相同或不同構造,示R0、鹵素、鹵化低級烷 基、-ORg、-0-鹵化低級烷基、-CN、或-N02、 Y :單鍵結合、低級伸烷基、低級伸烯基、或低級伸烷 基、 Z : -co2h或其生物學上之等效物、-conr7r8、或可具有 選擇自上述G1群中之基所取代之含氮雜環基、 R7及R8:可爲相同或不同構造,示氫原子、或可具有選擇 自下列G2群中之基取代之低級烷基、 G2群·· -ORG、-N(RG)2、-C02RG、及含氮雜環基、 但是不包括4— ({[N - [4 一氟苯基]磺酿基]一 N— (2—甲 氧基苯基)甘胺醯基]胺基}甲基)苯甲酸甲酯、以及N2- -15- 200817319 [(4 —氯苯基)礦醋基]一 N2 -(2,5 - 一氟苯基)一 N — [4 一(1,2,3 —噻二唑一 4一基)苯甲基]一 D-丙胺醯基。 以下皆相同]。 [4] 如同[3]項之化合物或其製藥學上容許之鹽,其 中,L1示單鍵結合。 [5] 如同[4]項之化合物或其製藥學上容許之鹽,其 中,A環示苯環。 [6] 如同[5]項之化合物或其製藥學上容許之鹽,其 中,X示單鍵結合。 [7] 如同[6]項之化合物或其製藥學上容許之鹽,其 中,L2及L3皆爲亞甲基。 [8] 如同[7]項之化合物或其製藥學上容許之鹽,其 中,Z示-C02H或其生物學上之等效物。 [9] 式(Π-A)所示磺胺化合物或其製藥學上容許之 鹽 【化9】
R (II-A) [式中之符號之意義如下:
R 10 R12 :可爲相同或不同構造,示鹵素、低級烷基、鹵 -16- 200817319 化低級院基、-O R ^、- Ο -鹵化低級院基、或_ R13 : R。、鹵素、鹵化低級烷基、-OR0、-〇 、或-CN、 B環:苯環、或芳香族雜環、 R14 : RG、鹵素、或-〇R〇、 V :氫原子、或低級烷基、 Y1 :單鍵結合、低級伸烷基、低級伸烯基 烷基-、 z1: C02H或其生物學上之等效物。以下皆丰 [1〇]如同[3]項之化合物或其製藥學上 中,選擇自下列群中: 4-[({Ν·(3-氯-2-甲苯基)-N-[(4-甲 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲苯基)-N-[(4-甲 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲苯基)-N-[(4-氯 甘胺醯基}胺基)甲基]苯甲酸、 3- [({N-(3-氯-2-甲苯基)-N-[(4-甲 甘胺醯基}胺基)甲基]苯氧基乙酸、
4- [({N-(3-氯-2-甲苯基)-N-[(4-甲 甘胺醯基}胺基)甲基]-N-(甲磺醯基)苯E 3-[({N-(3-氯-2·甲苯基)-N-[(4-氰 基]甘胺醯基}胺基)甲基]苯甲酸、 3-[({Ν-(3·氯-2 -甲苯基)-N-[(4-( _CN、 -鹵化低級院基 、或-0 -低級伸 目同]0 .容許之鹽,其 苯基)磺醯基] 苯基)磺醯基] 苯基)磺醯基] 苯基)磺醯基] 苯基)磺醯基] 戸醯胺、 <基苯基)磺醯 三氟甲基)苯 -17- 200817319 基]磺醯基}甘胺醯基)胺基]甲基}苯甲酸、 4- [({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]-2-甲氧基-N-(甲磺醯基)苯甲醯 胺、 3-[({.(2,3-二氯苯基)-1[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[({.(3_氯-2-甲氧基苯基)-心[(4-甲苯基)磺 醯基]甘胺醯基}胺基)甲基]苯甲酸、 3-[ ( {N- ( 3-溴-2-甲苯基)-N-[4-甲苯基)磺醯基]甘 胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲苯基)-N-[(4-乙苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-乙苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3_[({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]肉桂酸、 3-{3-[({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯 基]甘胺醯基}胺基)甲基]苯基}丙酸、 5- [({N-(3-氯-2-甲苯基)-Ν-[(4·甲苯基)磺醯基] 甘胺醯基}胺基)甲基]噻吩基-3-羧酸、 3-[({Ν-(3-氯-2-乙苯基)-Ν-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]肉桂酸、 3-{[(Ν-(3-氯-2 -甲苯基)-Ν-{[4-(三氟甲基)苯 基]磺醯基}甘胺醯基)胺基]甲基}肉桂酸、 -18- 200817319 3_[ ( {Ν· ( 3-氯-2-甲苯基)-N-[ ( 4-氯苯基)磺醯基] 甘胺醯基}胺基)甲基]肉桂酸、 3- ( 3-{[N- ( 3 -氯-2-甲苯基)-N-{[4-(二氣甲基)苯 基]磺醯基}甘胺醯基)胺基]甲基}苯基)丙酸、 3- [({N-(3-氯-2 -甲苯基)-N-[(2-氟-4 -甲苯基)磺 醯基]甘胺醯基}胺基)甲基]苯甲酸、 2-[ ( {N- ( 3·氯-2-甲苯基)-N-[ ( 4·甲苯基)磺醯基] 甘胺醯基}胺基)甲基]-1,3 -噁唑-4 -羧酸、 4- [ ( {N- ( 3-氯-2-甲苯基)-N-[ ( 4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]噻吩基-2-羧酸、 (2S) -2-{3-[({N-(3-氯-2-甲苯基)-N-[(4-甲苯 基)磺醯基]甘胺醯基}胺基)甲基]苯氧基}丙酸、以及 (2R) -2·{3·[({Ν-(3-氯-2-甲苯基)-N-[(4-甲苯 基)磺醯基]甘胺醯基}胺基)甲基]苯氧基}丙酸。 [11] 一種醫藥組成物,其特徵爲含有[3]項之化合物 或其製藥學上容許之鹽爲有效成份者。 [12] —種構成EP1受體拮抗劑之之醫藥組成物 〇 [1 3 ] —種構成下部尿道症狀之治療劑之[1 1 ]項之醫 藥組成物。 [14] 如同[13]項之醫藥組成物,其中,導致下部尿 道症狀之疾病係過動膀胱症、前立腺肥大症、膀胱頸部硬 化症、膀胱炎、或前立腺炎。 [15] 製造下部尿道症狀之治療劑用之[3]項之化合物 -19- 200817319 或其製藥學上容許之鹽之利用。 [16] 如同[15]項之用途,其中,導致下部尿道症狀 之疾病係過動膀胱症、前立腺肥大症、膀胱頸部硬化症、 膀胱炎、或前立腺炎。 [17] 包括投予治療有效量之[3]項之化合物或其藥學 上容許之鹽給病患者之下部尿道症狀之治療方法。 [18] 如同[17]項之治療方法,其中,導致下部尿道 症狀之疾病係過動膀胱症、前立腺肥大症、膀胱頸部硬化 症、膀胱炎、或前立腺炎。 又,本發明也包括下列項目: [19] 一種含有式(Ι-A)所示磺胺衍生物或其製藥學 上容許之鹽爲有效成份之EP1受體拮抗劑。 【化10】 R1
[式中之符號之意義如下: A環:苯環、環烷環、或芳香族雜環、 L1 :單鍵結合、或低級伸烷基、 L2 :低級伸烷基、 R1〜R4:可爲相同或不同構造,示氫原子、鹵素、低級烷 -20- 200817319 基、鹵化低級烷基、-OM、-Ο-鹵化低級烷基、-CN、 -N02、-CC^R0、-CO-低級烷基、·低級伸烷基-ORG、-低級 烷伸烷基-CC^V、亦可被取代之芳基、亦可被取代之雜芳 基、-〇-亦可被取代之芳基、-0-苯甲基、或-〇-亦可被取 代之雜芳基、 或R1和R2以及R3和R4,分別互相在苯環上,以及鄰接 在A環上之位置時,可和所結合之環上之碳原子成爲一體 ,形成5〜7節環烯環、或可選擇自下列G1群之基所取代之 雜環、 G 1群:低級院基、及氧代基、 R0 :氫原子、或低級烷基、 RA :氫原子、或低級烷基 RB :氫原子、低級烷基、-低級伸烷基-亦可被取代之 芳基、·低級伸烷基-亦可被取代之雜芳基、-低級伸烷基-〇-亦可被取代之芳基、或-低級伸烷基-0-亦可被取代之雜 芳基、 或RA及RB跟其所結合之氮原子成爲一體,形成含氮 雜環。以下皆相同]。 [20]式(H-B )所示磺胺衍生物或其製藥學上容許 之鹽。 -21 - 200817319 【化1 1】 R1
Η3JC L3
Υ-Ζ (ΙΙ-Β) R5 R6 [式中之符號之意義如下: Α環:苯環、環烷環、或芳香族雜環、 L 1 :單鍵結合、或低級伸烷基、 L2 :低級伸烷基、 R1〜R4 :可爲相同或不同構造,示氫原子、鹵素、低級烷 基、鹵化低級烷基、-ORG、-〇-鹵化低級烷基、-CN、 -N02、-CC^Rl -CO-低級烷基、-低級伸烷基-OR0、-低級 伸烷基-C〇2RG、亦可被取代之芳基、亦可被取代之雜芳基 、-0 -亦可被取代之芳基、-〇 -苯甲基、或-〇-亦可被取代 之雜芳基、 或R1和R2,以及R3和R4分別互相在苯環上及A環上之 鄰接位置時,可和所結合之環上之碳原子成爲一體,形成 5〜7節環烯環,或可具有選擇自下列G1群中之基取代之雜 環、 G 1群:低級烷基、及氧代基、 RQ :氫原子、或低級烷基、 L3 :低級伸烷基、 -22- 200817319 χ :單鍵結合、或-〇-、 Β:苯環、或芳香族雜環、 R5及R6 :可爲相同或不同構造,示氫原子、鹵素、低級烷 基、鹵化低級烷基、-ORG、-0-鹵化低級烷基、-CN、或 -Ν Ο 2、 Y :單鍵結合、低級伸烷基、低級伸烯基、或-0-低級伸烷 基-、 Z : -OC2R〇、-CONR7R8、-C0NH-S02-R9、或可爲選擇自 上述G1群之基取代之含氮雜環基、 R7及R8:可爲相同或不同構造,示氫原子、或可爲選擇自 下列G2群之基取代之低級烷基、 G2群:-OR0、及含氮雜環基、 R9 : -OV、及可爲選擇自-0-C0-低級烷基之基取代之低級 烷基、 但是不包括4一({[N—(4 —氟苯基)磺醯基]一 N-(2-甲氧基苯基)甘胺醯基]胺基}甲基)苯甲酸甲酯、以及N2 一 [(4 一氯苯基)磺醯基]一 N2 -(2,5 -二氟苯基)一 N 一 [4一(1,2,3 —噻二唑一 4一基)苯甲基]一 D—丙胺醯胺 。以下皆相同]。 發明之效果 本發明之有效成份之式(〇所示化合物或其製藥學 上容許之鹽,具有強力的EP1受體拮抗作用,因此,可提 供EP 1受體有關疾病,特別是下部尿道症狀之治療藥用途 -23- 200817319 【實施方式】 實施發明之最佳途徑 本發明詳細說明如下: 又,本發明之有效成份之式(I )所示化合物中包括 式(II)、式(II-A)、式(Ι-A)及式(II-B)所示化合 物,因此這些化合物在下文中總稱爲「本發明化合物」。 本說明書中,「低級」一詞倘無特別說明皆指碳數爲 1〜6個(下文中簡稱爲(^_6)之直鏈狀或歧鏈狀之烴鏈。 「低級烷基」乃指C i _6之烷基。具體例如甲基、乙基 、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁 基、正戊基、正己基等。較佳者爲碳數1〜3者,具體例如 甲基、乙基、異丙基。 「低級伸烷基」乃指將Ci_6烷基之任意位置之一個氫 原子去除而得之二價基。具體例如伸甲基、伸乙基、甲基 伸甲基、二甲基伸甲基、伸丙基等。其中以伸甲基、伸乙 基、伸丙基爲較佳,尤以伸甲基、伸乙基爲更佳。 「低級伸烯基」乃指任意位置上具有雙鍵結合之C2-6 之低級伸烷基。具體例如伸乙烯基、伸丙烯基、1 -伸丁 烯基、2-伸丁烯基等。其中以伸乙烯基爲較佳。 「環烷環」乃指〇之飽和烴環,又,可形成交聯環 。具體例如環丙烷、環丁烷、環戊烷、環己烷、環庚烷、 環辛烷、金剛烷、及降冰片烷等。其中,以環戊烷或環己 -24- 200817319 院爲較ί:±ι。「環丨兀基」乃指由上述環院環所構成之環基。 「5〜7節環嫌ί哀」乃指具有一個雙鍵結合之c5巧之烴 環。具體例如環戊烯、環己烯、環庚烯等。較佳之例如環 戊烯、環己烯,更佳之例如環戊烯。 「鹵素」乃指鹵素原子。具體例如氟、氯、溴。其中 ,以氟、氯爲較佳。 「鹵化低級烷基」乃指上述「低級烷基」任意一個以 上之氫原子被相同或不同之上述「鹵素」取代之基。具體 例如氟甲基、二氟甲基、二氟甲基、2,2,2—三氟乙基、 五氟乙基等。其中,以三氟甲基爲較佳。 「芳基」乃指C6_14之單環狀、雙環狀或三環狀芳香族 烴環基,包括和C5-7環烯環稠縮之環基。但是c5— 7環烯環 形成稠環時,其結合鍵在芳香環上。具體例如苯基、萘基 、茚滿基、四氫萘基、芴基等。其中,以苯基爲較佳。 「雜環」乃指含有1〜4個選擇自氧、硫及氮之雜原子 之4〜1 2節之單環狀、或雙環狀之飽和或不飽和環。不飽 和環包括芳香族雜環。又,構成環原子之硫或氮經氧化而 形成其氧化物或二氧化物也包括之。具體言之,單環狀之 例如吖丁啶、吡咯烷、哌啶、哌畊、嗎啉、硫代嗎啉、吖 庚環、二吖庚環、卩惡丁環、四氫呋喃、四氫卩比喃、1,3 -二噁茂、2,3 —二氫—1,4 —二—8 -羥喹啉、吡唑烷、呋 喃、噻吩、吡咯、咪唑、吡唑、噻唑、噁唑、異噻唑、異 噁唑、三唑、四唑、噻二唑、噁二唑、吡啶、吡畊、嘧啶 、嗒畊、三畊、2,3 -二氫一 1,3 —噁唑等,二環狀之例如 -25- 200817319 1,3 -苯駢二噁茂、2,3 —二氫—1,4 —苯駢二—8—羥喹啉 、吲哚、苯駢呋喃、苯駢噻吩、苯駢噁唑、苯駢異噁唑、 苯駢噻唑、苯駢異噻唑、苯駢咪唑、吲唑、苯駢三唑、喹 啉、異喹啉、1,2,3,4 一四氫喹啉、1,2,3,4一四氫異喹啉、 喹嚀啉、喹唑啉、酞畊等。其中,以單環狀之雜環爲較佳 。「雜環基」乃指由上述雜環所構成之環基。 「芳香族雜環」乃指上述「雜環」中,由下列中選擇 之環基。i)含有1〜4個選擇自氧、硫及氮等雜原子之單 環狀五或六節芳香族雜環、i i )由上述i )之芳香族雜環稠 合而成之二環狀雜環(但是稠合之兩個之芳香族雜環可互 爲相同或不同構造),及iii )由上述i )之芳香族雜環和 苯環或五〜七節環烷縮合而成之二環狀雜環。具體例如i )吡啶、吡畊、嘧啶、嗒畊、三畊、吡咯、呋喃、噻吩、 咪唑、吡唑、三唑、四唑、噁唑、異噁唑、噁二唑、噻唑 、異噻唑、噻二唑、i i )萘啶、咪唑駢吡啶、吡咯駢嘧啶 、噻吩駢吡啶、噻吩駢吡咯啉、iii )苯駢咪唑、苯駢呋喃 、苯駢噻吩、苯駢噻二唑、苯駢噻唑、苯駢異噻唑、苯駢 噁唑、苯駢異噁唑、喹啉、異喹啉、5,6,7,8 —四氫喹啉、 5,6 5 7,8 —四氫異喹啉、喹唑啉、喹噶啉、酞畊、吲哚、異 吲哚、四氫苯駢咪唑、色滿、吲唑等。其中,以上述i ) 或iii)爲較佳,尤以上述i)之單環狀五或六節環香族雜 環爲更佳。「雜芳基」乃指上述芳香族雜環所構成之基。 「含氮雜環」乃指上述「雜環」中’構成環之元素中 至少含有一個以上之氮原子之雜環。具體例如吡咯啶、哌 -26- 200817319 啶、哌畊、嗎啉、噻嗎啉、吖丁啶、二吖丁啶、i,2,3,4一 四氫喹啉、1,2,3,4 一四氫異喹啉、吡啶、吡畊、嘧啶、嗒 畊、三D并、吡咯、咪唑、吡唑、三唑、四唑、噁唑、異噁 唑、噁二唑、噻唑、異噻唑、噻二唑、苯駢咪唑、苯駢噻 二唑、苯駢噻唑、苯駢異噻唑、苯駢噁唑、苯駢異噁唑、 喹啉、異喹啉、5,6,7,8—四氫喹啉、5,6,7,8 —四氫異喹啉 、喹唑啉、喹of啉、酞畊、吲哚、異吲哚、四氫苯駢咪唑 、吲唑等。「含氮雜環基」乃指上述含氮雜環所構成之環 基。 「-C02H或其生物學上之等效物」乃指羧酸或具有和 羧酸相同之電子或立體配置,具有共同之生物學性狀之其 他原子或原子團。這些包括業者一般使用之所謂羧酸生物 等配物,被保護之羧基、或羧酸藥物前體等,具體例如羧 酸、羧酸酯、異羥肟酸(-CO-NH-OH)、醯基氨腈 (-CO-NH-CN)、醯基氨磺醯(-C0-NH-S02-R或 -S02-NH-CO-R )、或四唑、5 —氧代—1,2,4 —噁二唑、3 —羥基異噁唑、5 -氧代—1,2,4 —噻二唑、3 -羥基一 1,2,5 —噻二唑、3 -羥基一 r 一吡喃酮等。其中,以羧酸 、醯基氨磺醯、四唑、或5 —氧代一 1,2,4 一噁二唑爲較佳 。尤以羧酸或醯基氨磺醯爲更佳。 又,醯基氨磺醯(-CO-NH-SOrR 或-S02-NH-C0-R) 中之R之例如羥基、·〇·低級烷基及-0-CO-低級烷基所構成 群中選擇之基可取代之低級烷基。 「可具有取代基」乃指「不具有取代基」、或「由1 -27- 200817319 〜5個相同或不相同之取代基所取代,其中以1〜2個取代 基所取代爲較佳」。 又,如同-N(RG)2中之RG等有複數個基存在時,各個 分別之基(此處指)可互爲相同或不相同之構造。 R 1〜R4之「亦可取代之芳基」、「亦可被取代之雜芳 基」、「-0 -亦可被取代之芳基」、「〇_亦可被取代之雜 芳基」中之「芳基」及「雜芳基」中,其容許之取代基之 例如選擇自下列G3群中之基; G3群:鹵素、低級烷基、鹵素低級烷基、-OR0、-〇-鹵素 低級院基、-Ν Ο 2及-C N。 RB之「-低級伸烷基-亦可被取代之芳基」、「-低級 伸烷基-亦可被取代之雜芳基」、「-低級伸烷基-〇-亦可 被取代之芳基」、及「-低級伸烷基-0-亦可被取代之雜芳 基」中之「芳基」及「雜芳基」中,其可被容許之取代例 如選擇自上述G3群中之基,-0-苯甲基、-N(Rg)2、 -N(Rg)-CO-低級烷基、-N(Rg)-S02-低級烷基、-S(〇)n-低 級烷基、,可具有選擇自上述G3群中之基取 代之苯基、-低級伸烷基-〇RG、或-Y-Z。 本發明之有效成份(I )中之較佳形態如下: (1-a) L1以單鍵結含爲較佳。 (2_a) L2以伸甲基爲較佳。 (3-a) A環以苯環爲較佳。 (4 - a ) R 1及R2可爲相同或不同構造,以鹵素、低級 烷基、鹵化低級烷基、-0RQ、-〇-鹵化低級烷基、-CN、或 -28- 200817319 -no2爲較佳,以鹵素、低級烷基、或-oM爲更佳,尤以氯 、溴、甲基、乙基或甲氧基爲較佳。又,R1及R2之苯環上 之取代位置,以對於L1所結合之位置而言,2-位置及3-位 置皆爲上述所記載之相同或不相同之基取代爲較佳。 (5-a) R3及R4可爲相同或不相同構造,以RG、鹵素 、-CN、鹵化低級烷基、-CO-低級烷基、或-低級伸烷基 -OM爲較佳,以R〇、鹵素、-CN、或鹵化低級烷基爲更佳 ,尤以氫原子、甲基、乙基、溴、氯、氟、-CN或三氟曱 基爲最佳 ° 其中,以R3及R4之一方爲氫或氟,另一方爲上述之基 而氫及氟以外之基爲更佳。 (6_a) RA以氫爲較佳。 (7-a) RB以可爲-低級伸烷基-取代之芳基、或可爲_ 低級伸烷基-取代之雜芳基爲較佳,以可爲-伸甲基-取代 之芳基、或可爲-伸甲基-取代之雜芳基爲更佳。此處,芳 基以苯基爲較佳,雜芳基以噻嗯基、呋喃基、吡啶基或嘧 D定基爲較佳。又,可具有取代基之芳基及可具有取代基之 雜芳基以分別爲不具有取代基之芳基及雜芳基、或分別由 選擇自鹵素、_ORG、-〇_鹵化低級烷基、-CN、-低級伸烷 基- OR0、-N(RG)-C0-低級烷基及- γ_ζ所構成群中之基所取 代之芳基及雜芳基爲較佳。以分別爲不具有取代基之芳基 及雜芳基、或分別由選擇自-〇Μ及-Y-Z所構成群中之基取 代之芳基及雜芳基。 本發明之有效成份(I )之最佳形態乃上述(1 -a )〜 -29- 200817319 (7-a )所記載各個較佳之基組合而成之化合物。另一種 較佳形態爲式(II )所示化合物。 本發明化合物(II )之較佳形態如下: (1-b) L1以單鍵結合爲較佳。 (2-b) L2以伸甲基爲較佳。 (3-b) A環以苯環爲較佳。 (4-b ) R1及R2可爲相同或不同構造,以鹵素、低級 烷基、鹵化低級烷基、-ORQ、-〇-鹵化低級烷基、或-CN爲 較佳,以鹵素、低級烷基、或-〇RG爲更佳,尤以氯、溴、 甲基、乙基或甲氧基爲最佳。R1及R2在苯環上之取代位置 以對於L 1所結合之位置而言,2 -位置及3 -位置皆爲相同或 不相同之上述之基所取代爲較佳。 (5-b ) R3及R4可爲相同或不同構造,以、鹵素、 鹵化低級烷基、-ORG、-0-鹵化低級烷基或-CN爲較佳,以 、鹵素、鹵化低級烷基或-CN爲更佳,尤以氫、甲基、 乙基、溴、氯、氟、-CN或三氟甲基爲最佳。 R3及R4之一方爲氫或氟,另一方爲選擇自上述之基且 氫及氟以外之基爲更佳。 (6-b ) L3以伸甲基或伸乙基爲較佳,以伸甲基爲更 佳。 (7-b) X以單鍵結合爲較佳。 (8-b ) B環以苯環、噻吩環、呋喃環、噁唑環、吡啶 環或嘧啶環爲較佳,以苯環、噻吩環或噁唑環爲更佳。 (9-b ) R5及R6可爲相同或不同構造,以Ro、鹵素、 -30- 200817319 或-OV爲較佳,以氫、或鹵素爲更佳,尤以R5及R6皆爲氫 、或一方爲氫而另一方爲氟爲最佳。 (10-b ) Y以下列形態爲較佳:i ) Z爲-C02H、或其 生物學上之等效物、或-CONR7R8時,Y爲單鍵結合、伸乙 基、伸乙烯基、伸丙烯基、-0-伸甲基-、或-0-甲基伸甲 基-、ii) Z可爲選擇自上述G1群中之基所取代之含氮雜環 基時,γ可爲單鍵結合。 (1 1-b ) Z以-C02H或其生物學上之等效物爲較佳, 以- C02H、醯基氨磺醯、四唑或5 -氧代—1,2,4 —噚二唑 爲更佳,尤以-C02H或-C0NH-S02Me爲最佳。 本發明化合物(II )之最佳形態爲上述(1-b )〜( 1 1 -b )所述各較佳之基所組合而成之化合物。 本發明化合物(Π-Β )中之較佳形態如下: (1 ) L 1以單鍵結合爲較佳。 (2 ) L2以伸甲基爲較佳。 (3 ) A環以苯環爲較佳。 (4 ) R1及R2可爲相同或不同構造,以鹵素、低級烷 基、鹵化低級垸基、-0 RG、- Ο -鹵化低級院基、-C N、或 -N〇2爲較佳,以鹵素、低級烷基、或-0rG爲更佳。又,R1 及R2在苯環上之取代位置,以對於L1所結合之位置而言, 鄰位及間位皆爲相同或不同之上述之基取代爲較佳。 (5 ) R3及R4可爲相同或不同構造,以氫、低級烷基 、鹵素、-CN、鹵化低級烷基、-C0_低級烷基、或-低級伸 烷基-〇Μ爲較佳,以甲基、乙基、溴、氯、-CN、三氟甲 -31 - 200817319 基、乙醯基、或羥甲基爲更佳。尤以R3及R4之一方爲氫, 另一方爲上述中氫以外之基爲最佳。 (6 ) L3以伸甲基或伸乙基爲較佳,以伸甲基爲更佳 〇 (7) X以單鍵結合爲較佳。 (8 ) B環以苯環、噻吩環或吡啶環爲較佳,以苯環爲 較佳。 (9 ) R5及R6可爲相同或不同構造,以氫或-〇-低級烷 基爲較佳,以皆爲氫、或一方爲氫且另一方爲-0-低級烷 基爲更佳。 (10) Y 以 i ) Z 爲-CO2R0、-CONR7R8、或-CONH-S02-R9時,Y爲單鍵結合,伸乙基、伸乙烯基、或_〇_伸甲 基,ii) Ζ爲選擇自上述Gi群中之基所取代之含氮雜環基 時,Y爲卓鍵結合’爲較佳。 (11) Z以- C02H、-CONH-(CH2)2〇H、 -CONH-(CH2)2NMe2、-C0NH-S02Me或 -CONH-S〇2-(CH2)3〇H爲較佳。 本發明化合物(II )之另一種最佳形態爲上述(1 ) 〜(1 1 )所述各種較佳之基所組合之化合物。 本發明化合物隨取代基之種類可能存在有幾何異構物 或互變異構物之情形,本發明包括該異構物之分離者或混 合物。 又,本發明化合物具有不對稱碳原子時,據此可能存 在有(R ) 、'( S )等光學異構物。本發明化合物包括該 -32- 200817319 光學異構物之混合物或純離者全部。 加之,本發明化合物也包括藥理學上容許之藥物前體 。藥理學上容許之藥物前體乃指藉加溶劑分解,或生理學 條件下具有可轉成本發明之NH2、OH、C02H等基之化合 物。形成藥物前體之基,例如記載於「Pr〇gress in Medicine」Life-Science、Medica公司出版,1 98 5 年,第 5 卷,2157〜2 161頁或「醫藥品之開發(第7卷)分子設計 」,廣川書店出版,1990年,163〜198頁等之基。 本發明化合物隨酸加成鹽或取代基之種類,可能和鹼 形成鹽之情形。該鹽爲製藥學上容許之鹽,具體例如鹽酸 、溴氫酸、碘氫酸、硫酸、硝酸、磷酸等之無機酸、甲酸 、乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸 、乳酸、蘋果酸、酒石酸、枸櫞酸、甲磺酸、乙磺酸、天 冬胺酸、谷胺酸等之有機酸所形成酸加成鹽、鈉、鉀、鎂 '錦、鋁等之無機鹽、甲胺、乙胺、乙醇胺、賴胺酸、烏 胺酸等之有機鹽所形成鹽或銨鹽等。 加之,本發明化合物或其鹽之各種水合物或溶劑合物 及結晶等也包括在本發明化合物範圍。 製造方法 本發明化合物或其製藥學上容許之鹽,可依據其基本 _造或取代基之種類之特徵,使用各種周知之合成方法而 # XQ 5: °該時’視官能基之種類,就製造技術上之效果而 H ’將該官能基在原料至中間體之階段用適當之保護基保 -33· 200817319 護,或容易轉換成爲該官能基之基取代爲佳。該官能基之 例如胺基、羥基、羧基等,其保護基之例如T. w. Greene 及 Ρ· G. Μ· Wuts 等人所著「Protective Groups in Organic Synthesis (有機合成中之保護基)」(美國),第3版, (John Wiley & Sons公司),1999年中所記載之保護基, 視反應條件選擇適宜者而利用。使用該方法時,在導入該 保護基而行反應後,必要時去除保護基,或轉換爲所欲形 態之基而得所期待化合物。 又,本發明化合物之藥物前體跟上述保護基之情形同 樣,可在原料至中間體之階段,導入特定之基,或使用所 得本發明化合物進行反應而製成。該反應可採用一般酯化 、醯胺化、脫水等業者周知方法而進行。 本發明化合物之典型的製造方法說明如下。惟本發明 之製造方法並非侷限於下述範圍。 (製法1 ) 【化1 2】
本步驟乃將化合物(IV )和化合物(III )或其反應 性衍生物反應而製造本發明化合物(I )之步驟。該反應 -34- 200817319 性衍生物之例如醯鹵化物(醯氯、醯溴等)、酐(跟氯碳 酸乙酯、氯碳酸苯甲酯、氯碳酸苯酯、對-甲苯磺酸、異 戊酸等反應而得混合酐、或對稱狀酐)、活性酯(可爲硝 基或氟原子等親電子基取代之酚、1 -羥基苯駢三唑( HOBt ) 、N-羥基琥珀醯亞胺(HONSu)等所製成酯類)
、低級烷酯、醯基疊氮等。該反應性衍生物可藉一般方法 製成。該反應乃將等莫耳或一方爲過量之羧酸化合物( m )或其反應性衍生物和化合物(iv ),在芳香族烴基 、鹵化烴類、醚類、N,N —二甲基甲醯胺(DMF ) 、N,N —二甲基乙醯胺(DMA ) 、N —甲基吡咯烷酮(NMP )、 乙酸乙酯或乙腈等對於反應不活性之溶劑中,冷卻〜加熱 溫度範圍下進行。視反應性衍生物之種類,爲順利進行反 應,在驗(採用三乙胺、二異丙基乙胺、N—甲基嗎琳、 〇比Π定、4 一 ( N,N —一甲胺基)卩比Π定等)之存在下反應較 爲有利。吡啶尙可兼溶劑之用途。 使用游離羧酸時,宜使用縮合劑(例如N,N,-二環己 基碳化二亞胺(DCC )、1— [3 — (二甲胺基)丙基]一 3 —乙基碳化二亞胺(WSC ) 、1,1’ —羰基二咪唑(CDI ) 、N,N’— 一號拍醯亞胺碳酸酯、Bop試劑(Aldrich公司製 品,美國)、2— (1H —苯駢三卩坐—1 一基)一1,1,3,3 — 四甲基糖醛酸四氟化硼酸酯(TBTU) 、2— ( iH —苯餅三 唑一 1 —基)一 1,1,3,3 —四甲基糖醛六氟磷酸酯(HBTU ) 、二苯基磷酸疊氮化物(DPPA )、磷醯氯、三氯化磷、 三苯基膦/ N -溴化琥珀醯亞胺等),有時還要使用添加 -35- 200817319 劑(例如HONSu、HOBt等)有益於反應之進行。 (製法2 ) 【化1 3】 R1
(I) (上式中,Lv2示脫離基。以下皆相同)。 本步驟乃係將化合物(VI )以具有脫離基之化合物( V )加以烷化而製造本發明化合物(ϊ )之步驟。L v2所示 脫離基乃親核取代反應中常用之脫離基就行,例如氯、溴 等之鹵素、甲磺醯氧基、對-甲苯磺醯氧基、三氟甲磺醯 氧基等之磺醯氧基、低級烷磺醯基、芳磺醯基之磺醯基等 皆可適用。本步驟中之烷化反應可採用業者一般使用之烷 化方法。例如無溶劑中’或苯、甲苯、二甲苯等之芳族烴 類、乙酸乙醇等之酯類、二乙醚、四氫呋喃(THF)、二 噁烷等之醚類、二氯甲烷、1,2-二氯乙烷、氯仿等之鹵 化烴類、DMF、DMA、NMP、二曱亞楓(DMS0 )、乙腈 等對於反應不活性之溶劑、或醇類等之溶劑中,室溫至加 熱迴流下進行反應。隨化合物種類也可在有機鹽(例如三 -36- 200817319 乙胺、二異丙基乙胺、N —甲基嗎啉、吡啶、4 — ( N,N — 二甲胺基)吡啶較爲適用)、或金屬鹽鹼(例如碳酸鉀、 碳酸鉋、氫氧化鈉、氫氧化鉀、氫化鈉、第三丁氧基鉀等 較爲適用)之存在下進行,對於順利進行反應較爲有利。 (製法3 ) 【化14】
(上式中,Lv1示脫離基。以下皆相同)。 本步驟乃將化合物(VII)以化合物(VIII)磺醯化 而製成本發明化合物(I )之步驟。Lvi之脫離基以氯、溴 等之鹵素爲較適用。該反應可適用上述文獻「Pr〇tective Croups in Oirganie Synthesis」所述磺醯化條件而進行。 具體而言’無溶劑下,或THF、二氯甲烷、乙腈等溶劑中 ,必要時還在三乙胺、吡啶等鹼之存在下,冷卻下至加熱 迴流溫度下進行。 (製法4 ) -37- 200817319 【化1 5】
(上式中,ALK示低級烷基。以下皆相同)。 本步驟乃由Z示酯基之本發明化合物(Il-a )經水解 而製成Z示羧基之本發明化合物(II _b )之步驟。本步驟 之水解反應例如可按照上述「Protective Groups in Organic Synthesis」所記載之脫保護反應而進行。 另外,式(I )及式(II )所示若干化合物,可如同 上述由製得本發明化合物藉下述製造例,實施例所記載方 法及其改變方法、或業者一般採用之周知之烷化、醯化、 取代反應、氧化、還原、水解、脫保護等步驟加以任意調 配而製造之。 本發明化合物之製造上所使用原料化合物,例如可按 照下述方法,周知方法或其改變方法而容易製成。 (原料合成1 ) -38- 200817319 【化1 6】
(III) 第一步驟: 本步驟乃將化合物(IX)以化合物(VIII)磺醯化而 製成化合物(VI )之步驟。本步驟之磺醯化可按照前述製 法3之磺醯化相同方法進行。 第二步驟: 本步驟乃將化合物(VI )以具有脫離基之化合物(X )進行烷化而製造化合物(XI )之步驟。本步驟之烷化可 按照前述製法2之烷化相同方法進行。 第三步驟: 本步驟乃經水解由化合物(X1 )製造化合物(111 ) 之步驟。本步驟之水解反應可按照上述製法4之水解反應 相同方法進行。 -39- 200817319 (原料合成2 ) 【化1 7】
0 (V) (上式中,Lv3示脫離基。 本步驟乃將化合物 ΧΠ)醯化而製成化合物 以T皆相同)。 ‘ )以具有脫離基之化合物( (V )之步驟。Lv3所示脫離基之 例如氯、溴等鹵素爲較適用。該反應例如可適用上述「 Protective Groups in Organic Synthesis」所記載之醯化條 件。具體而言,在無溶劑下,或THF、二氯甲烷、乙腈等 之溶劑中,必要時再於三乙胺、吡啶等鹼之存在下,冷卻 至加熱迴流溫度下進行反應° (原料合成3 ) 【化1 8】
本步驟乃將化合物(IX )以具有脫離基之化合物(v )烷化而製成化合物(v 11)之步驟。本步驟之烷化可按 -40- 200817319 照上述製法2之烷化相同方法進行。 上述各製法所得反應產物,可做爲游離化合物,其鹽 或水合物等各種溶劑合物而分離、精製之。該鹽可藉一般 造鹽處理方法而製造之。 該分離、精製可藉萃取、濃縮、蒸餾、結晶化、過濾 、再結晶處理、各種層析法等一般化學操作而進行。 各種異構物可利用異構物間之物理化學性質之差異而 藉一般方法分離之。例如光學異構物可藉一般光學離析法 ,例如分級結晶法或層析法等分離之。又,光學異構物可 利用適當之光學活性之原料化合物製造之。 本發明化合物之有效性藉下列試驗確認。 (1 )使用EP 1受體表達細胞之受體掊抗活性之測定試驗 能安定地表達鼠EP1受體之HEK 293細胞(American Type Gultixre Collection提供),在試驗前日以2x 1 04細胞 /well狀分注於96 well聚-D-離脫酸-塗佈板(商品名爲 Biocoat PDL96W Beack/clear,日本貝登迪根遜公司製品 ),在37°C,5%二氧化碳(C02)下,於含有1〇%牛胎 兒血清(FBS)之培養基(商品名爲DM EM,In Vitro gen 公司製品)中培養一夜。培養基以負荷緩衝液(含有4 # Μ之螢光標識試劑(商品名爲Fluo3-AM、同仁堂公司製品 ):漢克氏平衡鹽溶液(HBSS ) 、20mM 2 - [4— ( 2—羥 乙基)—1 一哌畊基]乙磺酸(HEPES ) —氫氧化鈉( NaOH ) 、2.5mM之羥苯磺胺(probenecid) 、〇·1% 牛血 -41 - 200817319 清白蛋白(BSA ))取代,在室溫下靜置3小時之後,使 用安置有洗淨溶液之洗板機(商品名爲ELx405,BIO-TEK 儀器公司製品)洗淨細胞。添加用洗淨溶液先行溶解、稀 釋之化合物,然後,安置在細胞內鈣(Ca )濃度測定裝置 (商品名爲FLIPR,Moleculor Device公司製品)中。5分 鐘後添加PGE2使其最後濃度爲ΙΟΟηΜ,然後,測定細胞內 鈣濃度之變化。計算細胞內鈣濃度變化之最大値及最小値 之差距,做爲測定値而保存之。添加ΙΟΟηΜ之PGE2做爲0 %,添加緩衝液時之反應做爲100%時,計算其50%阻礙 濃度做爲IC 5 〇値。 其結果示於下列表1中。又,表中之Pre乃代表下述製 造例號碼,Ex示下述實施例號碼。 [表1] 化合物 IC5〇(nM) _ 製造例1 16 _ 製造例1 5 12 一 實施例7 1.6 一 實施例1 6 2.4 一 實施例20 1.4 _ 實施例24 1 .0 一 實施例2 6 __2J__ 實施例3 8 1.5 _ 實施例40 0.72 一 實施例74 1.0 一 (2 )使用EP1受體表達細胞之受體結合試驗 鼠EP1受體乃係導入信號肽(MKTIIALSYIFCLVFA : -42- 200817319 序列號碼l )及FLAG序列(DYKDDDDK :序列號碼2 )於 N -末端之後’亞克隆化在表達載體(商品名爲PCEP4’ In Vitrogene公司製品)上。該鼠EP1表達載體使用轉染試劑 (商品名爲Fugene-6’ Roche Diagnostics公司製品)轉染 在 HEK293EBNA細胞(American Type Culture Collection )之後,在37°C,5%二氧化碳下’含有l〇%FBS之培養 基(商品名爲DMEM,In Vitro gene公司製品)中,培養2 日。回收培養後之細胞,使用細胞溶解液(含有2 0 m M三 個(羥甲基)胺基甲烷(Tris )緩衝液,pH 7·5、5mM乙 二胺四乙酸(EDTA ))處理細胞,藉超離心處理( 23000rpm,25分鐘,2次)粗調整S旲標品。 含有調整好之膜標品(15 // g)及3H-PGE2之反應液( 150//1,組成份:10mM 2— (N —嗎啉基)乙磺酸(MES )/氫氧化鉀(KOH) ,pH 6.0、ImM EDTA,10mM 二氯 化鎂(MgCl2) ^ 0.02% 3 - [(3 —膽醯胺丙基)二甲銨 基]丙磺酸(CHAPS ))在室溫下保溫培養1小時。反應藉 冰冷之緩衝液終止,減壓下吸引過濾、捕捉結合之 3H-PGE2於玻璃濾器(商品名爲Uniniter-96,GF/B, Perkin-Elmer公司製品),使用微閃煉(商品名爲 Microscinti 20,Perkin-Elmer公司製品)藉微板閃煉計數 器(商品名爲Topcoun-ter5Packard公司製品)測定結合放 射活性。 從分散標繪圖求得解離係數(Kd )値及最大結合量 (Bmax )値[參照 Annal s of the New York Academy of -43- 200817319
Science,(美國),1949年,第 51 卷,660頁)。非專一 性結合在過剩量(2.5// M)之非標識PGE2之存在下以其 結合量而求得。化合物所造成3H-PGE2結合阻礙作用之測 定,藉添加2·5ηΜ之3H-PGE2及化合物而進行。 各化合物之阻礙係數Ki ( nM )依照下式求得。
Ki = IC50/ ( 1 + ( [C]/Kd )) 上式中,[C]示反應系中所使用3H-PGE2之濃度。 其結果示於下列表2中。 [表2] 化合物 Ki(nM) 製造例1 0.68 實施例7 0.57 實施例1 6 1.00 實施例2 0 0.74 實施例3 8 0.48 實施例4 0 0.33 實施例74 0.35 (3 )對於乙酸誘致頻尿鼠之作用 利用病態模式檢討化合物之抗頻尿作用。經乙酸處理 鼠之膀胱內而造成膀胱黏膜之障礙’已知可活化侵害刺激 傳遞求心性神經(參考The Journal of Neuroscience,( 美國),1 992年12月,第12卷,第12期,4878〜89頁)。 由乙酸處理膀胱內部可誘致頻尿狀態,所以能評估對於該 症狀之藥效。 -44- 200817319 本試驗使用體重爲200〜45 0g之Wistar系雄鼠(查理 斯利拜公司提供)。在戊巴比妥麻醉下(50mg/kg、i.p·) 切開腹部正中央露出膀胱,使用安裝有27G之注射針之注 射筒去除膀胱內之殘尿。然後,注射0.5〜0.7ml之1%乙 酸溶液於膀胱內,再閉合創傷口。2日後進行試驗。放入 鼠於代謝籠內,馴化1小時後,投予被檢驗用藥,連續測 定隨後6小時之排尿重量變化。由總排尿量和總排尿次數 之商,計算出有效膀胱容量。其結果,乙酸處理膀胱內群 ,較之假手術群其有效膀胱容量減少,而呈現頻尿狀態。 另一方面,本發明化合物表現改善頻尿狀態之藥效。 由上述試驗(1 )〜(3 )之結果,確知本發明化合物 具有強力之EP 1受體拮抗作用,以及改善頻尿狀態之良好 效果。因此,本發明化合物做爲EP 1受體有關疾病,特別 是下部尿道症狀之治療藥用途甚爲有用。 本發明中所指造成下部尿道症狀之疾病,例如過動膀 胱、前立腺肥大症、膀胱頸部硬化症、膀胱炎、前立腺炎 等。 本發明中所指下部尿道症狀,包括例如白天頻尿、夜 間頻尿、尿意急迫感、急迫性失禁等蓄尿症狀、尿勢下降 、排尿中斷、排尿延緩等之排尿症狀及殘尿感等之排尿後 症狀、膀胱痛、尿道痛、外陰部痛、陰囊痛、骨盤痛等之 性器官或下腹部痛等症狀。加之,上述蓄尿症狀、排尿症 狀及排尿後症狀還包括伴隨前立腺肥大症所造成蓄尿症狀 、排尿症狀及排尿後症狀。又,蓄尿症狀包括伴隨過動膀 -45- 200817319 胱、膀胱炎及前立腺炎所造成蓄尿症狀。 含有1種或2種以上之本發明化合物或其鹽爲有效成份 之製劑,使用一般製劑化所用載體或賦形劑或其他添加劑 而調製之。 投予方式可任意爲使用錠劑、九劑、膠束劑、顆粒劑 、散劑、液劑等之經口投予、或靜脈注射、肌肉注射等之 注射劑、栓劑、經皮膚劑、經鼻腔劑或吸入劑等之非經口 投予等各種形態。投予量視症狀、病患年齡、性別等而決 定其適量。一般,經口投予時,成人一日投予0.001 mg/kg 〜100mg/kg左右,經一次或分爲2〜4次投予之。靜脈投予 時,一般,成人一次計在〇.〇〇〇lnig/kg〜l〇mg/kg範圍下, 一日投予1次至複數次。又,經鼻腔投予時,一般,成人 次計使用〇.〇〇〇lnig/kg〜10mg/kg範圍下,一日投予一次 〜複數次。又,吸入投予時,一般,成人一次計,投予 O.OOOlmg/kg〜lmg/kg範圍下,一日投予一次〜複數次。 本發明之經口投予用固體組成物,可使用錠劑、散劑 、顆粒劑等。該固體組成物中,由一種或一種以上之活性 物質,混合以例如乳糖、甘露糖糖、葡萄糖、羥丙基纖維 素、微晶狀纖維素、澱粉、聚乙烯吡咯烷酮、矽酸鋁酸鎂 等之至少一種不活性賦形劑而成。該組成物可依照一般方 法,含有例如硬脂酸鎂等之潤滑劑或羧甲基澱粉鈉等之崩 解劑、溶解輔助劑等不活性添加劑。又,錠劑或九劑在必 要時尙可使用糖衣劑或腸溶性塗佈劑被膜而成。 經口投予用之液體組成物包含藥劑上容許之乳劑、液 -46- 200817319 劑、懸濁劑、糖漿劑、酏劑等,也包含例如精製水、乙醇 等一般常用之不活性溶劑。該組成物除不活性溶劑之外, 尙可含有潤濕劑、懸濁化劑等輔劑、甘味劑、矯味劑、芳 香劑、防腐劑等。 非經口投予用之注射劑包含無菌之水性或非水性之液 劑、懸濁劑、乳劑。水性溶劑包含例如注射用蒸餾水及生 理食鹽水。非水性溶劑包含例如丙二醇、聚乙二醇、橄欖 油等植物性油、乙醇等醇類、吐溫80 (藥方名稱)等。該 組成物尙可含有等滲劑、防腐劑、潤濕劑、乳化劑、分散 劑、安定化劑、溶解助劑等。該溶劑例如利用濾菌用濾器 ,配合殺菌劑或放射線照射而進行無菌處理。又,尙可製 成無菌之固體組成物,使用前以無菌水或無菌之注射用溶 劑溶解、懸濁而利用。 外用劑包括軟膏劑、硬膏劑、乳霜劑、凍膠劑、泥敷 劑、噴霧劑、洗滌劑、點眼劑、眼用軟膏劑等。該外用劑 包含一般常用之軟膏基劑、洗滌基劑、水性或非水性之液 劑、懸濁劑、乳劑等。該軟膏基劑或洗滌基劑例如包括聚 乙二醇、丙二醇、白色凡士林、白蠟、聚氧化乙烯硬化蓖 麻籽油、硬脂酸甘醇酯、硬脂醇、鯨蠟醇、聚氧乙烯月桂 醇醚、倍半油酸山梨聚糖等。 吸入劑或經鼻腔劑等之經黏膜劑可使用液狀或半固狀 者’可依照一般周知方法而製成。尙可適當添加例如乳糖 或澱粉等賦形劑、pH調整劑、防腐劑、界面活化劑、潤 滑劑、安定劑或增黏劑等。投予時可利用適當地吸入或吹 -47- 200817319 送用裝置。例如使用計量投予吸入裝置等周知之裝置或噴 霧器’以化合物單獨或經配方之混合物等粉末、或調配以 醫藥上容許之載體成爲溶液或懸濁液而投予。乾燥粉末吸 入器可利用一次投予用或複數次投予用者,也可利用乾燥 粉末或含粉膠囊。或利用例如氯氟烷、氫氟烷或二氧化碳 等適當氣體爲射出劑,以加壓氣溶噴霧等形態投予。 製造例及實施例 本發明化合物之製造方法藉下列製造例及實施例具體 說明,惟本發明不侷限於該製造例及實施例範圍。又,本 發明化合物之原料化合物之製造方法藉參考例說明之。 又’參考例’製造例及實施例中之符號代表以下所示 意義(下文中皆相同)。
Rf :參考例號碼、Pre :製造例號碼、Ex :實施例號 碼、Str :構造式、Syn :製造方法(數字代表以該號碼爲 實施例號碼之該實施例化合物相同,以相對應之原料所製 造。數字之前附有R字時代表以該號碼爲參考例號碼之參 考例化合物相同,以相對應之原料所製造,又,數字之前 附有P字時代表以該號碼爲製造例號碼之製造例化合物相 同,以相對應之原料所製造。又,例如,P 1 * 1之情形, 中間介以星字(* )而記載介由複數製造方法時,代表以 相對應之原料’將該反應自左或從上依照順序而製造), Dat :物理化學資料(El : EI-MS ( [M]+ ) ; EP : ESI-MS (Pos),未記載時代表[M + H]+) ; ΕΝ: ESI-MS (Neg) -48- 200817319 ([Μ-ΗΓ ) ; API : API-MS ( Pos )(未記載時代表 [M + H]+ ) ; FP : FAB-MS ( Pos )(未記載時代表[M + H] + );FN : FAB-MS ( Neg )(未記載時代表[M - H ] ·); NMRl:DMSO-d6 中之 1H-NMR 下之尖峰之 δ (ppm)); Me:甲基、Et:乙基、nPr:正丙基、iPr:異丙基、Bn: 苯甲基、Ac:乙醯基、Ms:甲磺醯基。 參考例1 溶解18.7g之3 —氯—2 —甲基苯胺於120ml之吡啶中, 以3 0分鐘時間少量分批加入22.9g之對-甲苯磺醯氯,在室 溫下攪拌一夜。減壓濃縮反應液,加入水於所得殘渣中, 再用乙酸乙酯萃取。有機層用1M鹽酸、飽和食鹽水、飽 和碳酸氫鈉水溶液、飽和食鹽水洗淨後,以無水硫酸鈉乾 燥。減壓蒸飽去除溶劑,而得3 4 · 6 g之N — ( 3 -氯一 2 —甲 苯基)一 4 一甲基苯磺醯胺。 參考例2 溶解34.5g之N— (3 —氯一2 —甲苯基)—4 —甲苯磺 醯胺於232ml之DMF,再加入21.4g之溴乙酸乙酯及19.3g 之碳酸鉀,在1 0 0 °C下攪拌1小時。反應液冷卻至室溫後, 加入水以乙酸乙酯萃取。有機層用食鹽水洗淨後,以無水 硫酸鈉乾燥。減壓蒸餾去除溶劑,所得殘渣使用矽膠管柱 層析法(己烷:乙酸乙酯=80: 20)進行精製,而得34.6g 之N— (3 —氯一 2 —甲苯基)一N— [(4 —甲苯基)磺醯 -49 - 200817319 基]甘胺酸乙酯。 參考例3 溶解35.8g之N— (3—氯—2 —甲苯基)一 N— [(4 — 甲苯基)磺醯基]甘胺酸乙酯於15.7ml之乙醇及157ml之1,4 —二噁烷中,加入157ml之1 Μ氫氧化鈉水溶液’用60 °C 整夜攪拌,將反應液冷卻至室溫後,減壓濃縮;再加入 1 Μ鹽酸調整爲酸性後,用乙酸乙酯萃取之。有機層用飽 和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓蒸餾去除溶劑 ,而得29.3g之Ν— (3 —氯一2—甲苯基)一Ν— [(4 —甲 苯基)磺醯基]甘胺酸。 參考例4 溶解7.42g之4-甲氧基苯甲胺於70ml之二氯甲烷中, 在-10 °C下滴加含有23· 2g之溴乙醯溴之二氯甲烷溶液( 10ml )。在下滴加含有8.0 ml之三乙胺之二氯甲烷溶液 (l〇ml )於反應液中。在室溫下攪拌30分鐘。反應液在冰 冷下加入水用二氯甲烷萃取。有機層用飽和碳酸氫鈉水溶 液洗淨後,以無機硫酸鎂乾燥。減壓蒸餾去除溶劑,所得 殘渣用5夕膠管柱層析法(己院:乙酸乙酯=9 0 : 1 0〜0 : 1 00 )進行精製,所得粗製物經由乙酸乙酯再結晶處理, 而得6.11g之2 —溴一N —(4 —甲氧基苯甲基)乙醯胺。 參考例5 -50- 200817319 溶解3.93g之3 -氯一 2-甲基苯胺於 加入2.00g之碳酸鉀之後’使用1小時分ί 之2一溴一 Ν— (4 一甲氧基苯甲基)乙醯 拌一夜之後。加入冰水’再用乙酸乙酯萃 食鹽水洗淨後,以無水硫酸鈉乾燥。減壓 所得殘渣用矽膠管柱層析法(己烷:乙圈 3 0: 70 )進行精製’而得2.8 9g之Ν2—( 基)一 N— (4—甲氧基苯甲基)甘胺醯胺 參考例6 溶解l.OOg之3 -氯一 2-甲基苯胺於 醯胺中,再加入1 .80g之碳酸氫鈉之後, 溴丙酸甲酯,在室溫下攪拌4小時。反應 二異丙醚萃取之。有機層用飽和食鹽水洗 酸鎂乾燥。減壓蒸餾去除溶劑,所得殘渣 法(己烷:乙酸乙酯=95 : 5〜8 5 : 25 ) 0.92g 之 N— (3 —氯一2 —甲苯基)一/3 — 參考例7 溶解〇.92g之N— (3 —氯—2 —甲苯基 於5ml之吡啶中,冰冷下加入1.1 9g之對一 室溫下攪拌一夜。反應液中加入水,用二 機層用1 Μ鹽酸、食鹽水、飽和碳酸氫鈉 以無水硫酸鎂乾燥。減壓蒸餾去除溶劑, 1 0ml 之 DMF 中, 比少量加入3.5 5 g 胺。在室溫下攪 取之。有機層用 蒸餾去除溶劑, I乙酯=70: 30〜 3 —氯一 2 —甲苯 10ml之六甲基磷 加入1 . 1 9 g之3 — 液中加入水,用 淨後,以無水硫 用矽膠管柱層析 進行精製,而得 丙胺酸。 )一 Θ -丙胺酸 甲苯磺醯氯,在 異丙醚萃取。有 水溶液洗淨後, 所得殘渣用矽膠 -51 - 200817319 管柱層析法(己烷:乙酸乙酯=90: 10〜70: 30)進行精 製,而得0.92g之N— (3 —氯—2 —甲苯基)一N— [(4 -甲苯基)磺醯基]一 /3 —丙胺酸甲酯。 參考例8 溶解652mg之4— {[(3—氯一 2 —甲苯基)胺基]磺醯 基}苯甲酸於10.0ml之THF中,在氬氣氛圍下,力卩入6.00ml 之1 Μ硼烷-THF配位化合物,在室溫下攪拌4小時。反應液 中加入1.0 0ml之水-乙酸混合液(1 : 1 )之後。加入水, 再用乙酸乙酯萃取。有機層用飽和碳酸氫鈉水溶液、飽和 食鹽水洗淨後,以無水硫酸鈉乾燥。減壓蒸餾去除溶劑, 而得467mg之N— (3 —氯一2—甲苯基)一 4—(經甲基) 苯磺醯胺。 參考例9 溶解83 Omg之4 —氰基吡啶一 2-羧酸甲酯於20· 0ml之 乙醇及20.0ml之氨水中,加入160mg之阮內鎳觸媒,在氫 氣氛圍下,室溫中攪拌4小時。反應液用矽藻土過濾,減 壓濃縮濾液,所得殘渣用矽膠管柱層析法(氯仿:甲醇 =10 : 1 )進行精製,而得410mg之4 —(胺基甲基)吡啶 一 2 -碳草釀胺。 參考例1 0 溶解20.0g之(3—氰基苯氧基)乙酸乙酯於l〇〇ml之 -52- 200817319 乙酸中,加入5.58ml之乙酸及4.00g之10%鈀-碳(川硏, AD型,含54%水),在氫氣氛圍下,室溫中攪拌一夜, 反應液用矽藻土過瀘,減壓濃縮濾液,所得殘渣用矽膠管 柱層析法(氯仿:甲醇=1 〇 : 1 )進行精製。溶解所得粗製 物於乙酸乙酯中,加入1 0.0 m 1之4 Μ氯化氫/乙酸乙酯溶液 ,在室溫下攪拌1小時。,濾取所析出結晶’用乙酸乙酯洗 淨後,減壓乾燥,而得6.49 g之[3 -(胺基甲基)苯氧基] 乙酸乙酯•鹽酸鹽。 參考例1 1 41mg之碘化銅、1.82g之磷酸三鉀、38mg之N,N’—二 甲基乙二胺、l.OOg之1— (4 —碘苯基)甲胺及510mg之2 —哌啶酮之混合物中,加入4.29ml之甲苯,在氬氣氛圍下 ,80 °C中攪拌一夜。反應液用矽藻土過濾後,減壓濃縮濾 液,所得殘渣用矽膠管柱層析法(氯仿:甲醇=1 〇 : 1 )進 行精製。而得5 52mg之1 — [4—(胺基甲基)苯基]哌啶—2 —酮。 參考例1 2 溶解5.00g之4-氟一3 —甲基苯甲酸於100 ml之乙醇中 ,加入2.5 9gml之濃硫酸之後,加熱迴流一夜。反應液冷 卻至室溫之後,減壓濃縮,所得殘渣在冰冷下加入飽和碳 酸氫鈉水溶液,調整爲鹼性(pH 8 )之後,用乙酸乙酯萃 取。有機層用食鹽水洗淨後,以無水硫酸鈉乾燥。減壓蒸 -53- 200817319 餾去除溶劑,而得5.86g之4 一氟一3—甲基苯甲酸乙酯。 參考例1 3 溶解3.00g之4一氟—3 一甲基苯甲酸乙酯於50.0ml之 四氯化碳中,加入4.40g之N—溴號拍酸亞胺及1.35g之2,2' -偶氮二異丁腈,加熱迴流4小時。反應液冷卻至室溫之 後,減壓濃縮。所得殘渣用砂膠管柱層析法(己院:乙酸 乙酯=7: 3)精製,而得1·73§之3一(溴甲基)—4一氟苯 甲酸乙酯。 參考例1 4 溶解1.5 6g之亞胺基二羧酸二第三丁酯於20.0ml之 DMF中,冰冷下加入804mg之第三丁氧基鉀,在室溫下攪 拌一小時。反應液中滴加含有1 · 7 0 g之3 —(溴甲基)—4 —氟苯甲酸乙酯之DMF ( 10.0ml)溶液,在室溫下攪拌一 夜。反應液傾注在水中,用乙酸乙酯萃取,有機層用食鹽 水洗淨後,以無水硫酸鈉乾燥。減壓蒸餾去除溶劑,而得 2.59g之3 - {[雙(第三丁氧基羰基)胺基]甲基}一4一氟苯 甲酸。 參考例1 5 溶解2.59g之3—{[雙(第三丁氧基羰基)胺基]甲基} —4 —氟苯甲酸於10.0ml之乙酸乙酯中,加入1〇.〇ml24M 氯化氫/乙酸乙酯溶液,在室溫下攪拌4小時。減壓下濃縮 -54- 200817319 反應液,所得殘渣中加入乙酸乙酯及己烷進行結 ,而得2.59g之3—(胺基甲基)一 4 —氟苯甲酸 酸鹽。 參考例1 6 懸濁3 74mg之60%氫化鈉於20.0 ml之二甲氧 ,在- 5°C下滴加1.91g之二乙基膦酸基乙酸乙酯 溫下攪拌1 〇分鐘,反應液在冰冷下滴加含有(3 苯甲基)氨基甲酸第三丁酯之二甲氧基乙烷(5. 液,在60 °C下攪拌4小時。反應液冷卻至室溫之 水,用乙酸乙酯萃取。有機層用食鹽水洗淨後, 酸鈉乾燥。減壓蒸餾去除溶劑,而得3 — {[(第 羰基)胺基]甲基}肉桂酸乙酯。溶解於5.〇〇ml之 中,加入8.50ml之4M氯化氫/乙酸乙酯溶液,在 拌6小時。濾取所析出沈澱物,用乙酸乙酯洗淨 下乾燥,而得1 . 7 1 g之3 —(胺基甲基)肉桂酸乙 鹽。 參考例1 7 溶解779mg之3 —(胺基甲基)肉桂酸乙酯於 乙醇中,加入80mg之10%鈀-碳(川硏,AD型) 氛圍下,室溫中攪拌3小時。反應液用砂藻土過 下濃縮濾液,而得773mg之3 — [3 -(胺基甲基: 酸乙酯。 晶化處理 乙酯•鹽 基乙院中 ,再於室 一甲醯基 00ml)溶 後,加入 以無水硫 三丁氧基 乙酸乙酯 室溫下攪 後,減壓 酯•鹽酸 5·0 0 ml之 ,在氫氣 濾,減壓 苯基]丙 -55- 200817319 參考例1 8 溶解670mg之5 —甲醯基一1—甲基一1H —吡略—2 — 羧酸甲酯於10.〇1111之丁1^中,在一20°(:下加入3 0311^之硼 氫化鈉,在-20 °C下攪拌30分鐘之後,再於0°C下再攪拌1 小時。反應液中加入飽和氯化銨水溶液,用乙酸乙酯萃取 。有機層用飽和碳酸氫鈉水溶液,食鹽水洗淨後,以無水 硫酸鈉乾燥。減壓蒸餾去除溶劑,而得592mg之5 -(羥 甲基)一1—甲基一1H —吡咯一 2 —羧酸甲酯。 參考例1 9 溶解590mg之5—(經甲基)一1 一甲基一1H — Π比咯一 2 —羧酸甲酯。770mg之酞醯亞胺、1.83g之三苯膦於 10.0ml之THF中,冰冷下加入2.75ml之偶氮羧酸二乙酯之 後,在室溫下攪拌一夜。反應液減壓下濃縮,所得殘渣用 矽膠管柱層析法(己烷:乙酸乙酯=3 : 1〜1 : 1 )精製, 而得650mg之5— [ ( 1,3 —二酮基—1,3 —二氫—2H —異吲 哚一 2 —基)甲基]一 1—甲基一 1H —吡咯一 2—羧酸甲酯。 參考例2 0 溶解 650mg 之 5— [ ( 1,3 —二酮基—1,3 —二氫—2H — 異吲哚一 2—基)甲基]—1—甲基一 1H —吡咯一 2 —羧酸甲 酯於20.0ml之甲醇中,加入l〇9mg之畊· 1水合物之後,在 室溫下攪拌一夜。減壓下濃縮反應液’所得殘渣中加入氯 -56- 200817319 仿,濾除不溶性物後,減壓下濃縮濾液’而得到294mg之 5—(胺基甲基)一 1 一甲基一1H—吡咯一2—羧酸甲酯。 參考例2 1 溶解4.86g之5— (羥甲基)噻吩一 3 —羧酸甲酯於 50.0ml之二氯甲院中。冰冷下加入4.12ml之硫醯氯。在室 溫下攪拌1 5小時。減壓下濃縮反應液’加入乙酸乙酯於所 得殘渣之後,以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨。 用無水硫酸鎂乾燥後,蒸餾去除溶劑,而得4.9〇g之5 一( 氯甲基)噻吩一 3—羧酸甲酯。 參考例2 2 溶解3.57g之3 —氰基酚於60.0ml之乙腈中,加入 5.81ml之2 —溴一2 —甲基丙酸乙酯及14.6g之碳酸鉋,加 熱迴流一夜。反應液冷卻至室溫之後,加入水’用乙酸乙 酯萃取,有機層用飽和食鹽水洗淨。以無水硫酸鎂乾燥之 後,蒸餾去除溶劑,殘渣用矽膠管柱層析法(己烷:乙酸 乙酯=9: 1)精製,而得6.75g之2 —(3—氰基苯氧基)一 2—甲基丙酸乙酯。 參考例9 6 溶解2.50g之3 —羥基苯甲醛、2.77g之L—(—)—乳 酸甲酯、6.44g之三苯膦於25.0ml之THF中,冰冷下加入 22.2ml之2.2M偶氮羧酸二乙酯/甲苯溶液之後,在室溫下 -57- 200817319 攪拌一夜。反應液中加入飽和碳酸氫鈉水溶液之後,用乙 酸乙酯萃取,有機層用飽和食鹽水洗淨後,以無水硫酸鎂 乾燥。減壓下蒸餾去除溶劑,所得殘渣用矽膠管柱層析法 (己烷:乙酸乙酯=7: 3〜1: 1)精製,而得1.67g之(2R )一 2—(3-甲醯基苯氧基)丙酸甲酯。溶解所得該(2R )—2— (3 —甲醯基苯氧基)丙酸甲酯於33.3 ml之甲醇中 ,冰冷下加入3 94mg之氫硼化鈉,攪拌30分鐘。反應液中 加入乙酸乙酯及水之後,以乙酸乙酯萃取。有機層用飽和 食鹽水洗淨後,以無水硫酸鎂乾燥之。減壓下蒸餾去除溶 劑。而得1.68g之(2R) — 2— [3 — (羥甲基)苯氧基]丙 酸甲酯。 參考例9 7 ί谷解300mg之(2R) — 2— [3 — (經甲基)本氧基]丙 酸甲酯,46 5mg之亞胺基二羧酸二第三丁酯、543mg之三 苯膦於3.00之甲苯中,冰冷下加入44 5mg之偶氮羧酸二異 丙酯之後,在室溫下攪拌一夜。減壓下濃縮反應液,所得 殘渣用矽膠管柱層析法(己烷:乙酸乙酯=95 : 5〜0 : 1〇〇 )精製,而得5 84mg之(2R) —2— (3— {[雙(第三丁氧 基羰基)胺基]甲基}苯氧基)丙酸甲酯。 按照上述參考例1〜22,96及97相同方法,使用相對 應之原料分別製造下列表3〜1 0所示參考例化合物1〜1 〇4 。該參考例化合物之構造,合成法及物理化學性狀資料示 於表3〜1 0。 -58- 200817319 製造例1 溶解707mg之N— (3—氯-2-甲苯基)-N-[(4-甲苯基)磺醯基]甘胺酸於8.00ml之DMF中,再加入3 02mg 之4 —甲氧基苯甲胺、324mg之HOBt、460mg之WSC,在室 溫下攪拌一夜。反應液中加入水,用乙酸乙酯萃取。有機 層用飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下蒸餾 去除溶劑,所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯 二4: 1)進行精製,而得881 mg之N2 - (3 —氯—2—甲苯 基)一N—(4 一甲氧基苯甲基)—N2— [(4 一甲苯基)擴 醯基]甘胺醯胺。 製造例2 溶解449mg之N— (3—氯—2—甲苯基)—4—氟苯磺 醯胺於3.00ml之DMF中,再力口入3 8 7 m g之2 —溴一N — ( 4 一甲氧基苯甲基)乙醯胺、20 7mg之碳酸鉀,在室溫下攪 拌一夜。反應液中加入碳酸氫鈉水溶液,用氯仿萃取,有 機層用食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下蒸餾去 除溶劑,所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯) 進行精製,所得粗製物由己烷/乙酸乙酯結晶處理,而得 466mg之N2— (3 —氯一2 —甲苯基)一N— (4 —甲氧基苯 甲基)—N2— [(4—氟苯基)磺醯基]甘胺醯胺。 製造例3 -59- 200817319 溶解200mg之N2— (3—氯一2—甲苯基)—N— (4 — 甲氧基苯甲基)甘胺醯胺於2.0ml之吡啶中,再加入含有 200mg之4 —羥基苯磺醯胺之二氯乙烷溶液(2.0ml)。在 8 0 °C下攪拌一夜。減壓下濃縮反應液,殘渣中加入水,用 乙酸乙酯萃取,有機層用1 Μ鹽酸及水洗淨後,以無水硫 酸鈉乾燥。減壓下蒸餾去除溶劑,所得殘渣用矽膠管柱層 析法(己烷··乙酸乙酯=7〇 : 30〜3 0 : 70 )進行精製之後 ,再用矽膠管柱層析法(氯仿:甲醇=1〇〇 : 〇〜97 : 3 )進 行精製,所得殘渣經由二異丙醚結晶處理,而得68mg之 N2— (3—氯一2 —甲苯基)一 N2— [(4—經基苯基)石寅釀 基]—N —(4 一甲氧基苯甲基)甘胺醯胺。 製造例4 溶解66 8mg之N— [4—(苯甲氧基)苯甲基]—N2 —( 3 —氯一 2—甲苯基)一 N2 — [(4 一甲苯基)磺醯基]甘月女 醯胺於5.00ml之甲醇及2.00ml之THF中,再力口入7〇mg之1〇 %鈀-碳(川硏,AD型,含54%水),在氫氣氛圍下’室 溫中攪拌6.5小時。反應液用矽藻土過濾,減壓下蒸耀濾 液去除溶劑。所得殘渣用矽膠管柱層析法(己烷:乙酸乙 酯=5 0 : 5 0〜3 0 : 7 0 )進行精製,所得粗製物經由乙醇/水 再結晶處理,而得3 73 mg之N2—( 3 —氯一 2 —甲苯基)一 N -(4 一羥基苯甲基)—N2 — [(4 一甲苯基)磺醯基]甘 胺醯胺。 -60- 200817319 製造例5 溶解 300mg 之 4— [( (3 —氯一2 —甲苯基){2— [(4 一甲氧基苯甲基)胺基]一 2-酮基乙基}胺基)擴醯基]苯 甲酸於5.00ml之THF中,再加入340mg之氯甲酸乙酯及 3 2 6mg之三乙胺,室溫下攪拌1小時。使用30分鐘滴加含 有3 60mg之硼氫化鈉之水溶液(〇.80ml ),在室溫下攪拌2 小時。加入8.0 ml之1 Μ鹽酸於反應液調整成酸性之後,使 用氯仿/甲醇(5 /1 )之混合溶劑萃取,以無水硫酸鈉乾燥 有機層。減壓下蒸餾去除溶劑,所得殘渣用矽膠管柱層析 法(氯仿:甲醇=1〇〇 : 〇〜90 : 10 )精製,所得粗製產物 經由二異丙醚結晶處理,而得1 1 8mg之Ν2 — ( 3 —氯一 2 — 甲苯基)一 N2— {[4— (羥甲基)苯基]磺醯基}—N— (4 一甲氧基苯甲基)甘胺醯胺。 製備例6 溶解 3 3 0mg 之 N2— (3—氯一2—甲苯基)—N2— [(4 一甲苯基)磺醯基]一 N-(吡啶一 4一基甲基)甘胺醯胺 於5.0ml之二氯甲烷中,加入1 66mg之間一氯過苯甲酸,在 室溫下攪拌4小時。加入飽和碳酸氫鈉水溶液於反應液, 用氯仿萃取。減壓下濃縮有機層,所得殘渣用矽膠管柱層 析法(氯仿:甲醇=9 9 : 1 )進行精製,所得殘渣再經由己 烷/乙酸乙酯結晶處理,而得179mg之N2— ( 3 —氯—2 —甲 苯基)—N2— [(4 —甲苯基)磺醯基]一 N - [(1—氧離子 基吡啶一 4 一基)甲基]甘胺醯胺。 -61 - 200817319 製造例25 溶解22 0mg之4_{[(3 —氯—2 —甲苯基)胺基]磺醯 基}苯甲酸甲酯於1.10ml之DMF中,再力卩入168mg之2—溴 一 N— (4—甲氧基苯甲基)乙醯胺,l〇〇mg之碳酸鉀,在 室溫下攪拌7小時。反應液中加入水,用乙酸乙酯萃取, 有機層用食鹽水洗淨後,以無水硫酸鈉乾燥之。減壓下蒸 餾去除溶劑,所得殘渣以矽膠管柱層析法(己烷:乙酸乙 醋=7: 3〜4: 6)精製,而得270mg之4— [( (3 —氯一 2 — 甲苯基)一 {2— [(4—甲氧基苯甲基)胺基]—2 —酮基乙 基}胺基)磺醯基]苯甲酸甲酯。溶解所得該4一 [( (3 - 氯一 2 —甲苯基)一 {2 — [(4 —甲氧基苯甲基)胺基]—2 —酮基乙基}胺基)磺醯基]苯甲酸甲酯於2.00ml之甲醇及 1.50ml之THF中,再加入1.05ml之1M氫氧化鈉水溶液,在 室溫下攪拌2日。加入1 Μ鹽酸於反應液調整爲酸性之後, 用氯仿/甲醇(5/1 )之混合溶劑萃取,有機層以無水硫酸 鎂乾燥。減壓下蒸餾去除溶劑,所得殘渣以矽膠管柱層析 法(氯仿:甲醇=100: 〇〜90: 10)進行精製,而得 204mg之4— [( (3 -氯一2 —甲苯基)《2— [(4 —甲氧基 苯甲基)胺基]一 2—酮基乙基}胺基)磺醯基]苯甲酸。 製造例3 3 按照製造例5所示相同方法,由24〇mg之3 — [ ( {N — (3—氯一 2_甲苯基)一 N〜[(4 一甲苯基)磺醯基]甘胺 -62- 200817319 醯基}胺基)甲基]苯甲酸製得l〇〇mg之N2— (3—氯—2 — 甲苯基)一 N— [3—(羥甲基)苯甲基]一 N2— [(4—甲苯 基)磺醯基]甘胺醯胺。 實施例1
溶解3 0 8mg之4 一 [({N— (3—氯一2—甲苯基)—N 一 [(4 一甲苯基)磺醯基]甘胺醯胺}胺基)甲基]苯甲酸 甲酯於5.00ml之甲醇及2.00ml之THF中,再加入2.40ml之 1 Μ氫氧化鈉水溶液,在室溫下攪拌一夜後,加入3.00ml 之THF於反應液中,在60 °C下攪拌4小時。反應液加以冰 冷,加入2.6 0ml之1 Μ鹽酸調整爲酸性後,使用氯仿/甲醇 (5/1 )之混合溶劑萃取,有機層以無水硫酸鈉乾燥。減 壓下蒸餾去除溶劑,所得殘渣用矽膠宫柱析法(氯仿:甲 醇=100: 0〜90: 10)進行精製,而得601mg之4—[({Ν —(3 -氯一 2—甲苯基)—N— [(4—甲苯基)磺醯基]甘 胺醯基}胺基)甲基]苯甲酸。 實施例2 溶解 185mg 之 4 — [ ( {N— 3 —氯一2 —甲苯基)一N—[ (4 一甲苯基)磺醯基]甘胺醯基}胺基)甲基]苯甲酸, 25mg之氯化銨,62mg之HOBt於2.00ml之DMF中,再加入 7 8mg之WSC,在室溫下攪拌一夜。反應液中加入水,用 乙酸乙酯萃取,有機層用水,磺酸氫鈉水溶液水洗淨後, 以無水硫酸鈉乾燥。減壓下蒸餾去除溶劑,所得殘渣用矽 -63- 200817319 膠管柱層析法(己烷:乙酸乙酯=20: 80〜〇: 100)進行 精製,所得粗製物從乙醇/水(9 5 : 5 )中結晶處理,而 得 89mg 之 4— [({N -(3 —氯—2 —甲苯基)一N— [(4 — 甲苯基)磺酸基]甘胺醯基}胺基)甲基]苯甲醯胺。 實施例3 溶解300mg之N2— (3 —氯—2 —甲苯基)一N— (4 — 羥基苯甲基)一 N2 - [(4 一甲苯基)磺醯基]甘胺醯胺於 2.00ml之DMF中,再加入llOmg之碳酸鉀,133mg之溴乙 酸乙酯,在室溫下攪拌一夜。反應液中加入水,用乙酸乙 酯萃取,有機層以飽和食鹽水洗淨後,用無水硫酸鈉乾燥 。減壓下蒸餾去除溶劑,所得殘渣用矽膠管柱層析法(己 烷:乙酸乙酯=60: 40〜30: 70)進行精製,而得370mg 之4 — [ ( {N — (3 —氯一2 —甲苯基)一N — [ ( 4 —甲本基 )磺醯基]甘胺醯基}胺基)甲基]苯氧基乙酸乙酯。 實施例4
溶解182mg之3 — [({N— (3 —氯一 2 —甲苯基)—N 一 [(4 一甲苯基)磺醯基]甘胺醯基}胺基)甲基]苯甲酸 於0.50ml之DMF中,再加入75mg之1,1,—羰基二咪唑,在 室溫下攪拌1小時。反應液中加入4 0 m g之甲磺醯胺及6 6 m § 之DBU,在50 °C下攪拌8小時。反應液中力□入2.50ml之1M 鹽酸調整爲酸性之後’用氯仿/甲醇(5 /1 )之混合溶液萃 取,有機層用無水硫酸鈉乾燥。減壓下蒸餾去除溶劑’所 -64- 200817319 得殘渣用砍膠管柱層析法(氯仿:甲醇=1 0 0 : 0〜9 5 : 5 ) 進行精製,而得207mg之3 — [({N—(3—氯—2 —甲苯基 )一 N— [(4 一甲苯基)磺醯基]甘胺醯基}胺基)甲基]一 N-(甲磺醯基)苯甲醯胺。 實施例2 3 0 溶解404mg之N2— (3—氯—2—甲苯基)—N— (3 — 氰基苯甲基)一 N2 - [(4 一甲苯基)磺醯基]甘胺醯胺於 8.08ml之乙醇中,再加入I20mg之羥基胺•鹽酸鹽及 0.24 lml之三乙胺,加熱迴流6小時。反應液冷卻至室溫後 ,用乙酸乙酯萃取,有機層用水及飽和食鹽水洗淨後,減 壓下濃縮之。溶解所得殘渣於5.00ml之DMF中,冰冷下, 加入88mg之吡啶及16 7mg之氯甲酸2 —乙基乙酯,在5°C下 攪拌1小時。反應液用水稀釋之後,以乙酸乙酯萃取,有 機層用水和飽和食鹽水洗淨後,以無水硫酸鎂乾燥之。減 壓下蒸餾去除溶劑,溶解所得殘渣於8.54ml之二甲苯中, 加熱迴流1 3小時。減壓下濃縮反應液,所得殘渣中加入氯 仿及己烷,濾取所析出沈澱物,所得粗製物經由乙醇/二 異丙醚再結晶處理,而得29 8mg之N2— ( 3 —氯—2 —甲苯 基)一 N2— [(4 —甲苯基)磺醯基]一 N— [3 - (5 -酮基 一 4,5 —二氫一 1,2,4一噁二唑一 3—基)苯甲基]甘胺醯胺 實施例2 3 1 -65- 200817319 溶解3 OOmg之N2 — ( 3 —氯—2 —甲苯基)—N — ( 3 - 氰基苯甲基)一 N2— [(4-甲苯基)磺醯基]甘胺醯胺於 5.0〇1111之0^^中,再加入12511^之疊氮化鈉及1031^之氯 化銨,在1 〇 〇 °C下攪拌6小時。減壓下濃縮反應液’所得殘 渣中加入水,用氯仿萃取。有機層以飽和食鹽水洗淨後’ 用無水硫酸鎂乾燥。減壓下蒸餾去除溶劑’所得殘渣用分 離薄層層析法(氯仿:甲醇=80 : 20 )進行精製,所得粗 製物從乙醇/二異丙醚中再結晶處理,而得82.6mg之N2 — (3—氯一2 —甲苯基)—N2— [(4 —甲苯基)礦釀基]—N 一 [3 —(2H -四唑一 5 —基)苯甲基]甘胺醯胺。 按照上述製造例1〜6、2 5及3 3以及實施例1〜4、2 3 0 及23 1所示相同方法,使用相對應之原料製造表1 1〜22中 所示製造例化合物1〜122及表23〜45中所示實施例化合物 1〜23 1。又,製造例化合物之製造方法及物理化學資料示 於表46〜48中,實施例化合物之製造方法及物理化學資料 示於表49〜56中。 -66- 200817319 【表3】
Rf Syn Str Dat Rf Syn Str Dat 1 R1 ότ FP:296 2 R2 Cl (VMe =ρ〇2Β (Ύ〇 FP:382 3 R3 j〇rr° FP:354 4 R4 BryXT FP:258 ,260 5 R5 &;γ^σ0Μβ EP:319 6 R6 Cl rVe 〜C〇2Me H EP:228 7 R7 Cl 0CX— W EP:403 [M+Na]+ 8 R8 ότ Sh El:311 9 R9 h2nXs^3^CONh2 EP:152 10 R10 HCl H2N 八 c〇2Et FP:210 11 R11 °r^ ..XT0 El:204 12 R12 f)Cl • Me^^C〇2Et El :182 13 R13 BrjClc〇2B El :260 14 R14 B〇c2NxJX^Lc〇^b FP:398 -67- 200817319 【表4】
-68- 200817319 【表5】
-69- 200817319 【表6】
-70- 200817319 【表7】
Rf Syn Str Dat Rf Syn Str Dat 51 R14 Λ β〇〇2ν^Λ〇〇2Β FP:398 52 R15 HCI i^S η2ν^ΑΛ0〇2Β FP:198 53 R13 Br\/C^c〇2Et F El :260 54 R14 B〇c2N^J^Lc〇2B F FP:398 55 R15 H2N^X^c〇2Et F FP:198 56 R18 H〇^X)^C02Me El:172 57 R14 Boc2N^C^C02Me FP:372 58 R15 HCI H2N^J^/^C02Me FP:172 59 R11 j〇^ NCA^ 、OH El :216 60 R9 η2ν^Λ^ 、oh El :221 [M+H]+ 61 R11 El:203 62 R9 n^X0H H,j〇r FP:208 63 R1 f^[ H ncAA^0H EN:225 • 64 R9 H2N^J〇Ls:fL^〇H FP:231 65 R1 ί^Ι H NC^^^S;N^^NMe2 El :254 _ + 66 R9 H FP:258 67 R14 Boc2N^J^^c°2Me FP:357 68 R15 HCI 〇 飞 H2N\AN^C02Me FP:157 -71 - 200817319 【表8】
Rf Syn Str Dat Rf Syn Str Dat 69 R12 Mexy〇〇2B El:170 70 R13 El :248 71 R14 Boc2N^LJ^C°2Et FP:386 72 R15 FP:186 73 R16 b〇cnhvJ〇^c〇2B FN:318 74 R16 HCI Me FP:220 75 R17 BccmjOjT—t FP:322 76 R16 HCI ^ Me H2N^A^kAc〇2Et FP:222 77 R13 Br^^N工 C02Me EP:231 78 R14 B〇C2N 丄 C02Me FP:368 79 r . R15 Ηα Λι H以人2Me FP:168 80 R11 八 t>〇H η2ν^Λ^ FP:207 81 R10 Me Me H2N^A〇Xc〇2B El :237 82 R1 έτ Sh FP:310 83 R1 ά: M^° EN:338 84 R1 Cl 6C 〇r FP:296 -72- 200817319 【表9】
-73- 200817319 【表1 〇】
-74- 200817319 【表1 1】
Pre Str Pre Str 1 Oc鉍山 Me办 2 |^YMe h r^Y〇Me Fi7g ° 3 Cl HO^6 4 [j^VMe H f^Y〇H s^NaJ Me^ 〇 5 Cl Cc科山 H〇\J〇T° 6 rSrMe h 广扒〇’ έ^χΝ^ Μβ^! 〇 7 όΟν^ 8 ί^ΥΜβ Η ί^Ι 。 9 &:VJp ργ¥°0 0Me 10 Cl |jYMe Η ΓΥό 0 -75- 200817319 【表1 2】
-76- 200817319 【表1 3】
Pre Str Pre Str 21 ΛΜβ Η Me^ 0Me 22 &:Vtcre Me^0° 23 0 24 Cl A^Me ^^OMe α鉍山 —办 25 |f^YMe η j^Y〇Me ηο2ο^ 〇 26 rSfMe H j^T〇Me c以。 27 O^xr W〇 28 rSfMe H J^V〇Me Xyl:0 f3c^^ 29 ί^ΥΜβ H J^V〇Me ΜβΟ^ 〇 30 (fS^Me H J^V〇Me EtiJS 〇 •77- 200817319 【表1 4】
Pre Str Pre Str 31 if^TMe H r^T〇Me 〜办。 32 &:w -W。。 33 0Cvu〇l〇h Me^r〇 34 35 όςΛΟ M w 〇 36 W〇 37 Me^〇° 38 άΐν^8 Me02c、^^0 0 XJ° 39 f^YMe H J^V〇Me H〇zCyyl> ° 40 l[^VMe H ^N^YN-^OBn Mejar〇 -78- 200817319 【表1 5】
Pre Str Pre Str 41 (fSrMe h ^Y〇Me Me^ 〇 42 [Γ^γΜΘ h j^v0Me j〇^ 〇 43 rSfCI H j^Y〇Me Mejyl 0 44 (PYB H ^Y〇Me Me^ 〇 45 JCT j〇rf0 46 fSrBr H J^Y〇Me Me^ 〇 47 H J^Y〇Me jyi:0 48 [fS^Me H J^V〇Me H°^〇f6 ° 49 fVMe Η ίΛΐ ^ΑΝ^γΝ^Λ^Λ〇Η nr^0 50 W 〇 -79- 200817319 【表1 6】
Pre Str Pre Str 51 [Γ^ΥΜΘ H f^YF 52 Me MeAJ〇 53 fVMe h ^Sr^YN、"^Oipr ° 54 (f^Me H ^S)J^YNn^^^NHAc 。 55 Cl δ〇νυ^°Μβ 〇=ν〇ί°° Me 56 ΐΓ^ΓΜθ H J^YCN Μβ^ 〇 57 rSfMe H f^Y〇CHF2 Me^ 〇 58 ΓΥδ 59 Cl Cc^iXr Ο"6 60 Cl A^Me r^N.〇Me Cc^Xr O -80- 200817319 【表1 7】
Pre Str Pre Str 61 (Γ^ΓΜβ h j^Y°Me 〇i。 62 Me^rv^°0 U° 63 As^Me ^^〇Me (X^uCr Clyyt° 64 O^〇r car ° 65 i^TMe H i^T〇Me CI^T0 66 f^VMe H j^y〇Me 〇2Ml ° 67 rSfMe H J^V〇Me O^fT^7 68 i^TMe H J^V〇Me aw〇 69 a〇J〇r^°° 70 ja0Me u^r° -81 - 200817319 【表1 8】
-82- 200817319 【表1 9】
-83- 200817319 【表2 0】
-84- 200817319 【表2 1】
-85- 200817319 【表2 2】
Pre Str Pre Str 111 Cl iVMe H 112 113 ΛΜβ H 114 (f^Y〇Me h r^y0Me iyi0 115 H j^V〇Me Me^ 〇 116 |ΡΥΜΘ h r^Y〇Me Mejyl 0 117 όΟγίΟ^ 118 &Me h Me^U6 119 6〇xis-2 W 〇 120 Cl w 〇 121 9· ίιΜβ d f^\ H k^S^YNv^^s4v^NMe2 Me^f ° . 122 rSfMe h Me^ 〇 -86- 200817319 【表2 3】
Ex Str Ex Str 1 &y 0 2 &:V^〇rc〇N" W〇 3 4 ί^ΥΜθ H Jf^L ^^N^yN^^^CONHMs J〇T6 0 5 dc^W— 6 (fVMe H fY"C〇2H uMl 〇 7 |j^VMe H k^N^YNj^Ac〇2H 8 άΐ^χίοο, W 〇 9 Cl (|YMe H J^jl ^^N^YNv^^C〇2H W 〇 10 rSrMe h Me^ 〇 -87- 200817319 【表2 4】
Ex Str Ex Str 11 5:Μβ H 12 ώ^Χ^ΟΟ,Η 13 Cl Me^ 14 rS^e H jy〇 0 15 kNjYN^^AC02H M W 0 16 rSfMe h 八 C〇2H j〇ri 0 17 rSfMe h ^S^^YN」^^C02Me Me W 0 18 rVe H nr— 。 19 0C5;^〇〇2H Me々r〇 20 Cl fVMe h i^rC0NHMs ^ViNaj Me^ 〇 -88- 200817319 【表2 5】
Ex Str Ex Str 21 6c)xic〇2H w 〇 22 rSfMe H ^^N>〇YNV^^^C〇2H W 〇 23 άΐ^^α〇〇2Η W 〇 24 M W 〇 25 ^0 26 Cl N=\ J0T〇 27 άΐν^002" Me^f〇 28 Cl A^Me H ^yCONHMs Me^ 〇 29 j〇ri0 30 |j^VMe H ^^^yNv^^C02Me jyi f3c^^ -89- 200817319 【表2 6】
Ex Str Ex Str 31 ί^ΥΜθ H jar〇 32 (VMe h s^NvAJ Mejyl 0 33 W。〇 34 35 o &νυ〇^ 36 ΛΜβ h rr— Me办。 37 ιί^Τ〇1 H jQT〇 38 Γ^Γ〇Μθ H ^^N^YN^^^C02H J(7?0 39 |f^TMe H 、^n^YnJ^co2h j〇ri0 40 Cl Me^ 〇 -90- 200817319 【表2 7】
-91 - 200817319 【表2 8】
Ex Str Ex Str 51 0 52 6cIvj〇^c〇2H W° 53 jar〇 54 55 0C4 為 l〇h Me^0 0 56 Cl (^ΝςγΗ^Ογϊ1^ΝΜβ2 w ° 0 57 dc^joV- W。。 58 w°° 59 &n^YH-^cg2h 0 60 9' |pVMe H r^N ^^^YNv^^CONH2 fY〇 -92- 200817319 【表2 9】
Ex Str Ex Str 61 w 〇 62 Et W 0 63 ί^Ύ’ H jTIl 八 co2h FX^ 〇 64 ό^χχ。、 Nd 65 Cl fVMe U r^| 八 C〇2H xy〇 下3。入^ 66 |j^VMe H M W 0 67 jO^。。 68 Cl °Y^N |[YMe H jf^jfN Mei>§ 〇 69 Cl O^^N'Me |jYMe h Me^ 〇 70 ώΝ^^λ0〇2Η Η〇〇σ"0 -93- 200817319 【表3 0】
-94- 200817319 【表3 1】
Ex Str Ex Str 81 Me^° 82 9' iiYMe h F W 〇 83 W ° 84 0C;^Xuc〇2H W 〇 85 Mej〇|0 86 心九- Et办。 87 成。 88 f &Μ^υα_ Me^ 〇 89 &:hn 為 hX 90 Me^ 〇 -95- 200817319 【表3 2】
Ex Str Ex Str 91 W 0 Μ 92 Cl 〇 r0H 93 0cN^YNjixc〇2H W a 94 ί^ΎΜθ H f^\ J〇T〇 F 95 iVe H a f3 W 0 96 Cl J^.Me 0^ν^υ^^λΧ〇〇2η Clnr° 97 Cl °Y^o (jYMe η r^YN^ Me^ 〇 98 ci °γ^ο 6^Xr。 xy〇 99 &;# Me^ TOO ci 〇V^> rSfMe h r^rN{ j〇rf° -96- 200817319 【表3 3】
-97- 200817319 【表3 4】
Ex Str Ex Str 111 々e 乂li>0H Mei> HC, 112 ? Mp 〇YV〇H rSf H f^Y (ΡΥδ ° HCI 113 人 Me "Ϊ>0Η Cc^vcQr W ° m Cl J^.Me ^^Sj^C02H Me^ 〇 115 116 &V^o2h Μ#。 117 rSfMe H f^il Te Me W 118 &^XUeCOjH Mexy^° °h〇2c^^vh2 Me NH 119 [f^fMe H p 人 co2h Me W 0 120 Cl f^VMe H i^li Me 八 C〇2H W 〇 -98- 200817319 【表3 5】
Ex , Str Ex Str 121 W。 122 dQuax。 Me>ar〇 123 Me^ 〇 124 rSfMe h ^^N^YNv^^C〇2H J〇T6 0 125 0 126 jT^fMe h jQ"〇 127 Me^ 〇 128 |pVMe h r^| CI^^N^YNx^^C02H Cl政 129 Mp^表, Me^ 130 MeA^OXc〇2H W 〇 -99- 200817319 【表3 6】
Ex 131 Str Ex Str c 丨 CW。 132 K Me w 〇 133 BriX^ac〇2H 0,^ 0 134 MW 135 Cl H xys〇 136 Cl Λρ"0ΗΗ π ^ΑΝςγΝν^Λ0〇2Η W 〇 137 Me (|ΥΜθ H Me^ 〇 138 &ν^ΤΗ-Λ〇ο2η j〇r?0 139 Me0YYMe h rn ^^^YNv^^C02H xy〇 140 rprMe h i^i MeO 人 j〇r^0 •100- 200817319 【表3 7】
Ex Str 142 Str 141 Me^ (^ΜΘ HjfX xy〇 143 c〇2h rVMe η n ni0 144 .OH ijfMe H jy〇 145 n〇2 liYMe H Me W O 146 ◎ ί^χΜβ H f\ 147 F fVF Η Π Me^ 〇 148 Me ([ΥΒΓ H j〇T§ 149 OMe (iY〇Me H Me^ 〇 150 Me rVC0NH2H a Xys〇 -101 - 200817319 【表3 8】
Ex Str Ex Str 151 〇 152 M W O 153 jy〇 154 5 .A M W Ο 155 (5Ν^^χε〇2Η J〇T6 0 156 Me jys〇 157 (ΓΥΒ Η Π) Me W 0 158 jy^> 159^ Me w ° 160 F ΓΗ H f^\ jy〇0 -102- 200817319 【表3 9】
-103- 200817319 【表4 0】
Ex Str Ex Str 171 172 [TVSMe H jy〇 173 SMe ά^υΟ^〇2Η Μβ^ 〇 174 rYC0NH2 h r^ii jy t0 175 nrNHAc η a jQT〇 176 NHAc [f] H f^jl W 〇 177 conh2 ά^Ν^Χ〇〇2Η M eW 0 178 Λ H xy〇 179 (Χςγί^Χλ— j〇r? 0 180 ^γΝ〇 ^ Μ# O -104- 200817319 【表4 1】
Ex Str Ex Str 181 rSrMe h vi’ 0 182 ifSrMe h ^%^YNx^^co2h CT〇 183 &^wjac〇2H 〇r§ 0 184 (T^TMe H W 〇 Me 185 [|^ΥΜθ H CT6 186 ff^fMe H f^\ k^N^N^^Ac〇2H %。 187 rSfMe H 〇r§ 0 188 0C)xic〇2H Me0 XJ° 189 rSfMe h CT° Me’ 190 0〇UXc〇2H MeCK^^。0 XJ° -105- 200817319 【表4 2】
Ex Str 1 Ex Str 191 cl。 192 〇 193 rSfMe h Acxyr 〇 194 &>jac〇2H ^0 195 69^。, ho2c、^^s 0 U° 196 (|^VMe H ca” 197 6cI^jac〇2H C〇i ° 198 rSrMe h 199 ώ^αχ0〇2Η W〇 200 r^rMe h Cxy"0 Me -106- 200817319 【表4 3】
Ex Str Ex Str 201 6cI^〇xc〇2H ΓΥί 0 202 -、AW ° Η H 203 rSfMe h r^i w。 204 (f^YMe h r^i BrX^0 ° 205 |j^YMe H cyc^° 206 ΓΥί 0 Me02C^^^ 207 rSf H 〇, 208 ifVMe h r^i ^^N"〇VNV^^C〇2H Me. 〇 ‘ H 209 Cl ώΝςγΝ^Χ0〇2Η a0j〇^ 〇 210 rSfMe h r^i ^^N"〇YN>^^^C〇2H crW0 -107- 200817319 【表4 4】
Ex Str Ex Str 211 Cl 〇ί 〇 ό 212 Cl Me(X〇L^^^^^c〇2H 213 〇Me 〔又i> Η Η 214 Γ〇Ί 如。 H 215 〇ar 0 216 0^n^mULXco2h 217 0Cn、h^c^c〇2H W〇 218 0CN、fJ^ds:〇2H Etnr〇 219 0^N^U〇^co2H JO:^ 220 ^Lci H s Me w ° -108- 200817319 【表4 5】
Ex Str Ex Str 221 A^0Me s Me^〇° 222 0^γ^Χχ)2Η JO*。。 223 c,^ 〇 224 Cl rVMe H ψ 八 co2h w 225 Et^ 〇 226 &^^a0i;〇2H Μβ^ί 〇 227 Cl xy〇 228 f^T〇Me H f^Tl Ψ 八 C〇2H xyi 229 (fSfMe H J^jl ψ 入 C02H W 〇 230 Me^ 231 ά;)χν.Ν 0 n、n’ Me^° H -109- 200817319 【表4 6】 Pre Syn Dat Pre Syn Dat 1 P1 FP:473 31 P2 FP:501 2 P2 FP:477 32 R1*P2 FP:545[M] + 3 P3 FP:475 33 P33 FP:473 4 P4 FP:459[M]+ 34 P1 FP:469 5 P5 FP:489 35 P1 EP:444[M]+ 6 P6 EP:460 36 P1 EP:445 7 P1 印:444 37 P1 EP:445 8 P1 FP:473 38 P2 EP:517 9 P1 FP:473 39 P25 FP:503 10 P1 FP:487[M]+ 40 P1 FP:549 11 P1 FP:487[M]+ 41 R1*P2 FP:457 12 P1 EP:523[M+Na]+ 42 P2 FP:517, 519 13 P1 FP:480[M]+ 43 P2 FP:493 14 P1 FP:445 44 P2 FP:453 15 P1 FP:445 45 P2 FP:484 16 P1 EP:549[M]+ 46 P2 FP:517,519 17 P1 FP:353 47 R1*P2 FP:465 18 P1 EP:443 48 P5 FP:489 19 P2 FP:487[M]+ 49 P4 FP:459 20 P2 FP:453 50 P1 FP:501 21 P1 FP:487[M]+ 51 P1 FP:461 22 P1 FP:487[M]+ 52 P1 FP:433 23 P1 FP:473 53 PI FP:501 24 P2 FP:539[M+Na]+ 54 P1 FP:500 25 P25 EN:501 55 P2 FP:530 26 P2 FP:493[M]+ 56 P1 EP:468 27 P2 FP:484 57 P1 FP:509 28 P2 FP:527 58 P1 FP:527 29 R1*P2 FP:489 59 R1*P2 EP:459 30 P2 FP:487[M]+ 60 R1*P2 EP:465 -110- 200817319 【表4 7】 Pre Syn Dat Pre Syn Dat 61 R1*P2 EP:473 92 P1 EP:536 62 R1*P2 EP:473 93 P1 EP:522 63 R1*P2 EP:493 94 P1 EP:489 64 R1*P2 EP:499 95 P1 EP:445 65 R1*P2 EP:499 96 P1 EP:433 66 R1*P2 EP:504 97 P1 EP:434 67 R1*P2 EP:535 98 P1 EP:450 68 R1*P2 EP:551 99 P1 EP:449 69 R1*P2 EP:552 100 P1 EP:449 70 R1*P2 EP:565 101 P1 EP:447 71 R1*P2 EP:552 102 P1 EP:483 72 P1 EP:457 103 P1 EP:499 73 P1 EP:457 104 P1 EP:494 74 P1 EP:457 105 P1 EP:457 75 P1 EP:501 106 P1 EP:471 76 P1 EP:459 107 P1 EP:475 77 P1 EP:461 108 P1 EP:535 78 P1 EP:461 109 P1 EP:528 79 P1 EP:477 110 P1 EP:535 80 P1 EP:477 111 P1 EP:447 81 PI EP:477 112 P1 EP:463 82 P1 EP:521 113 P1 EP:458 83 P1 EP:521 114 R1*P2 EP:489 84 PI EP:458 115 R1*P2 EP:464 85 P1 EP:486 116 R1*P2 EP:439 86 P1 EP:488 117 P1 EP:423 87 P1 EP:488 118 P1 EP:446 88 P1 EP:488 119 P1 FP:522 89 P1 EP:519 120 P1 FP:566 90 P1 EP:521 121 P1 FP:593 91 P1 EP:521 I 122 P1 EP:468 -111 - 200817319 【表4 8】 Pre Dat 1 NMR1:2· 31 (3H, s),2.42 (3H,s), 3. 71 (3H,s),4· 05-4.32 (4H, m),6· 72 (1H, d, J=8.1Hz), 6. 78 (2Hf d, J=8. 2Hz), 6. 91 (2H, d, J=8.1Hz), 7.13 (1H, t, J=8.1Hz ),7.38-7.48 (3H, m),7. 54 (2H,d, J=7. 7Hz),8· 33 (1H,brs) 2 NMR1:2.31 (3H, s), 3. 71 (3H, s), 4.1 (2H, d, J=4.0Hz), 4.17 (1H, d, J=16Hz), 4 .27 (1H,d, 6Hz), 6_ 76-6· 8 (3H, m), 6.93 (2H, d, J=8· OHz),7.15 (1H,t, J=8 .OHz), 7.43-7.48 (3H, m), 7. 72-7. 76 (2H, m),8. 35 (1H, t, J=6. OHz) 3 NMR1 : 2.32 (3H, s), 3. 70 (3H, s), 4.02 (1H, dr J=15.4Hz), 4.07-4.14 (2H, m) ,4. 25 (1H, d, J=15. 3Hz), 6. 72 (1H, d, J=7. 9Hz), 6. 78 (2H, d, J=8.6Hz), 6. 8 9一6· 92 (4H, m),7· 13 (1H,t, J=8. OHz),7· 43 (1H,d, J=8. OHz),7. 47 (2H,d, J =8. 7Hz), 8.31 (1 Hf t, J=5.8Hz), 10.58 (1 Hr s) 4 NMR1 : 2. 28 (3H, s) r 2.42 (3H, s), 4.02-4.04 (2H, m), 4.08 (1H, dr J=15. 5Hz) ,4. 26 (1 Hf d, J=15.4Hz) f 6. 61 (2H, dt J=8. 5Hz), 6. 72 (1H, df J=7.1 Hz), 6. 7 8 (2Hr d, J=8. 6Hz), 7.13 (1H; t, J=8. OHz), 7. 40-7. 42 (3H, m) r 7.54 (2H, d, J =8. 3Hz) f 8. 26 (1H, t, J=5. 8Hz), 9. 25 (1H, s) 5 NMR1 : 2. 31 (3H, s), 3. 71 (3H, s), 4.08-4.12 (3H, m), 4. 28 (1Hr df J=15.4Hz) f 4. 62 (2H, d, J=5. 7Hz), 5.47 (1H, t, J=5. 7Hz), 6. 72 (1 Hr df J=7.8Hz), 6. 78 (2Hf d, J=8. 7Hz), 6. 91 (2H, d, J=8. 5Hz), 7.13 (1H, t, J=8. OHz), 7.45 (1Hr d ,J=7. 9Hz), 7. 53 (2H, d, J=8· 4Hz), 7. 62 (2H,d, J=8· 3Hz), 8. 34 (1H, t, J二5. 8Hz) 6 NMR1 : 2. 29 (3Hr s), 2.42 (3H, s), 4.1-4.16 (3Hr m), 4.32 (1 Hf d, J=8. OHz), 6 .74 (1H, d, J=4. OHz), 6. 98 (2H, d, J=3. 5Hz), 7.15 (1H, t, J=4. OHz) ,7.41-7 .46 (3H, m), 7. 54 (2H, d, J=4.1 Hz), 8. 06 (2H,d, J=3. 5Hz),8. 54 (1H, t,J=3H z) 15 NMR1 : 2. 29 (3H, s) f 2.42 (3H, s), 4.19 (1 Hf df J=15. 7Hz), 4.25-4.27 (2H, m) ,4. 37 (1H, df J=15. 7Hz), 6. 76 (1H, dr J=7. 6Hz) f 6. 96 (1H, df J=5. 2Hz) ,7.1 5 (1 Hr t, J=8.1 Hz), 7.42 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=8.3Hz), 7. 56 (2Hf d, J=8.3Hz), 8. 61-8. 66 (2H, m), 9.04 (1H, df J=1.4Hz) 19 NMR1 : 2. 28 (3H, s), 2.41 (3H, s), 3. 7 (2H, s), 3. 73 (3Hf s), 4.01 (2H, d, J=5. 7Hz), 4.46 (2H, s), 6.85 (2H, d, J=8.7Hz), 7.03 (2H, df J=8. 7Hz), 7.12-7.1 4 (1H, m), 7.2 (1H, d, J=6. 8Hz), 7. 36-7. 37 (3H, m), 7. 73 (2Hf d, J=8.2Hz), 8 _08(1H,t,J=5.8Hz) -112- 200817319 【表4 9】 Ex Syn Dat Ex Syn Dat 1 1 EP:487 31 P1 FP:529 2 2 EP:486 32 P1 EP:520 3 3 EP:567[M+Na]+ 33 P1 EP:510 4 4 FP:564 34 P1 EP:528 5 1 EP:539[M+Na]+ 35 P1 EP:526 6 1 EP:501 36 P1 EP:517 7 1 FP:487 37 P2*1 FP:506 8 P1*1 FN:488 38 R1*P2*1 FP:503 9 P1*1 FN:504 39 P2*1 FP:533 10 2 FP.486 40 P2*1 FP:501 11 P1*1 FP:501 41 P2*1 FP:487 12 P1*1 FP:501 42 P2*1 FP:501 13 P1*1 FP:501 43 R1*P2*1 FP:502 14 P1*1 FP:515 44 P2*1 EP:557 15 P2*1 EP:501 45 R1*P2*1 FP:513 16 3*1 EN:514 46 P2*1 EN:486 17 P1 EN:499 47 P1*1 EP:488 18 P1*1 EN:515 48 P1*1 EP:493 19 P1*1 FP:501 49 P1*1 EP:493 20 4 FP:564 50 P1*1 EP:513 21 1 FP:497 51 P1*1 EN:513 22 1 EN:539 52 P1*1 EP:513 23 1 FP:515 53 P1*1 EN:513 24 P1 FP:501 54 4 EP:608 25 P1 EP:508 55 2 FP:530 26 P1 FP:509 56 2 EP:557 27 P1 EP:516 57 2 EP:530 28 4 FP:594 58 2 FP:557 29 P2 FP:512 59 P2*1 FP:494 30 P2 FP:555 60 P1 FP:487 -113- 200817319 【表5 0】 Ex Syn Dat Ex Syn Dat 61 P1*1 EP537 91 2 EP:560 62 P1*1 EP:531 92 2 EP:560 63 P1*1 FP:521 93 P1*1 EP:505 64 P1*1 EP:528 94 P1*1 EP:505 65 P1*1 FP:571 95 P1*1 FP:547 66 P1*1 EP:488 96 P1*1 FP:513 67 P1*1 EP:494 97 P1 FP:542 68 P1 EP:540 98 P1 EP:553 69 P1 EP:555 99 P1 FP:542 70 P2*1 EN:501[M]* 100 P1 FP:556 71 P2*1 FP:488 101 4 FP:578 72 P1*1 FP:505 102 4 FP:592 73 P1*1 FP:529 103 4 FP:608 74 P1*1 FP:527 104 P1 FN:552[M]- 75 P1*1 EN:529 105 P1*1*4 FP:575 76 P1*1 EN:488 106 P1*1*4 FP:578 77 P1 FP:527 107 P1*1*4 FP:584 78 P1*1 EP:567 108 PI*1*4 FP:618 79 P1*1 EN:531 109 P1 EP:538 80 2*1 EP:544 110 P1 FP:581 81 P1*1 EP:505 川 P1 FP:543 82 P1*1 EP:569 112 P1 EP:554 83 P1*1 EP:535 113 P1 FP:596 84 P1*1 FP:529 114 P1*1 EP:478 85 P2*1 FP:505 115 P1*1 EP:477 86 P1*1 EP:527 116 P1*1 EP:493 87 P2*1 FP:505 117 P1*1 EP:527 88 P1*1 EP:505 118 P1*1 EP:529 89 2 FP:560 119 3*1 EP:531 90 2 EP:560 120 3*1 EP:531 -114- 200817319 【表5 1】 Ex Syn Dat Ex Syn Dat 121 P1*1 EP:489 15.1 R1*P2*1 EP:479 122 P1*1 EP:545 152 R1*P2*1 EP:493 123 R1*P2*1 EP:439 153 R1*P2*1 EP:522 124 R1*P2*1 EP:471 154 R1*P2*1 EP:478 125 R1*P2*1 EP:471 155 R1*P2*1 EP:478 126 R1*P2*1 EP:471 156 R1*P2*1 EP:453 127 R1*P2*1 EP:487 157 R1*P2*1 EP:467 128 R1*P2*1 EP:487 158 R1*P2*1 EP:467 129 R1*P2*1 EP:487 159 R1*P2*1 EP:457 130 R1*P2*1 EP:487 160 R1*P2*1 EP:457 131 R1*P2*1 EP:487 161 R1*P2*1 EP:473 132 R1*P2*1 EP:531 162 R1*P2*1 EP:473 133 R1*P2*1 EP:531 163 R1*P2*1 EP:517 134 R1*P2*1 EP:531 164 R1*P2*1 EP:469 135 R1*P2*1 EP:491 165 R1*P2*1 EP:469 136 R1*P2*1 EP:517 166 R1*P2*1 EP:455 137 R1*P2*1 EP:467 I 167 R1*P2*1 EP:483 138 R1*P2*1 EP:469 168 R1*P2*1 EP:469 139 R1*P2*1 EP:483 169 R1*P2*1 EP:469 140 R1*P2*1 EP:483 170 R1*P2*1 EP:497 141 R1*P2*1 EP:483 171 R1*P2*1 EP:464 142 R1*P2*1 EP:521 172 R1*P2*1 EP:485 143 R1*P2*1 EP:497 173 R1*P2*1 EP:485 144 R1*P2*1 EP:483 174 R1*P2*1 EP:482 145 R1*P2*1 EP:498 175 R1*P2*1 EP:496 146 R1*P2*1 EP:518 | 176 R1*P2*1 EP:496 147 R1*P2*1 EP:475 177 R1*P2*1 EP:482 148 R1*P2*1 EP:531 178 R1*P2*1 EP:481 149 R1*P2*1 EP:499 179 R1*P2*1 EP:522 150 R1*P2*1 EP:496 180 R1*P2*1 EP:524 -115- 200817319 【表5 2】 Ex Syn Dat Ex Syn Dat 181 R1*P2*1 EP:437 207 R1*P2*1 EP:559 182 R1*P2*1 EP:465 208 R1*P2*1 EP:559 183 R1*P2*1 EP::473 209 R1*P2*1 EP:565 184 R1*P2*1 EP:477 210 R1*P2*1 EP:565 185 R1*P2*1 EP:479 211 R1*P2*1 EP:565 186 R1*P2*1 EP:479 212 R1*P2*1 EP:579 187 R1*P2*1 EP:479 213 R1*P2*1 EP:589 188 R1*P2*1 EP:487 214 R1*P2*1 EP:601 189 R1*P2*1 EP:493 215 R1*P2*1 EP:566 190 R1*P2*1 EP:503 216 P1*1 EP:513 191 R1*P2*1 EP:503 217 P1*1 EP:547 192 R1*P2*1 EP:474 I 218 P1*1 EP:507 193 R1*P2*1 EP:515 219 P1*1 EP:511 194 R1*P2*1 EP:517 220 P1*1 EP:513 195 R1*P2*1 EP:517 221 P1*1 EP:509 196 R1*P2*1 EP:523 222 P1*1 EP:539 197 R1*P2*1 EP:527 223 P1*1 EP:551 198 R1*P2*1 EP:529 224 P1*1 EP:585 199 Ri*P2*1 EP:541 225 P1*1 EP:545 200 R1*P2*1 EP:544 226 P1*1 EP:549 201 R1*P2*1 EP:545 227 P1*1 EP:551 202 R1*P2*1 EP:545 228 P1*1 EP:547 203 R1*P2*1 EP:549 229 P1*1 EP:575 204 R1*P2*1 EP:551 230 230 EP:527 205 R1*P2*1 EP:555 I 231 231 EP:511 206 R1*P2*1 EP:559 | -116- 200817319 【表5 3】 Ex Dat 1 NMR1: 2· 31 (3H,s), 2.42 (3H, s), 4.12 (1H, d,J=15· 4Hz), 4· 18-4_ 19 (2H,m) ,4.33 (1H,d, J=15.4Hz), 6. 73 (1H,d,J=7. 8Hz),7· 06 (2H, d, J=8.2Hz),7.1 5 (1H, t, J=8.0Hz), 7.42 (2H,d,J=8.2Hz),7.45 (1H, d, J=8.2Hz), 7.55 (2H, d, J=8.3Hz), 7. 79 (2H, d, J=8. 2Hz), 8.50 (1H, t, J=6. OHz), 12. 74 (1H, b r s) 2 NMR1 : 2. 31 (3H, s), 2.42 (3Hf s), 4.12-4.15 (4H, m), 6. 75 (1H, d, J=7. 7Hz), 7.05 (2H, d, J=8.2Hz), 7.14 (1H, tr J=8. OHz), 7.3 (1H, brs), 7.41 (2H, d, J= 8. 2Hz), 7· 46 (1H, d, J=7. 8Hz), 7.55 (2H,d, J=8.3Hz), 7. 73 (2H, d, J=8· 2Hz ),7. 9(1H, brs),8.47(1H, t, J=5.9Hz) 4 NMR1 : 2. 30 (3H, s), 2.42 (3H, s), 3. 36 (3H, s), 4.13 (1H, d, J=15.6Hz), 4. 23 (2H, d, J=5. 9Hz) r 4. 30 (1H, dr J=15. 6Hz), 6. 74 (1H, d, J=8. OHz), 7.12 (1 Hr tr J=8. OHz), 7. 2(1H, d, J=7. 7Hz), 7. 36 (1H, d, J=7. 6Hz) r 7. 39-7.44 (3H, m ),7. 54 (2H,d, J=8. 3Hz), 7. 72 (1H, s), 7. 77 (1H, d, J=7. 8Hz), 8. 5 (1H, t, 5.9Hz) J2.11(1H,brs) 5 NMR1:2. 32 (3H, s),2. 41 (3H,s),4. 03-4· 04 (4H,m),4. 26 (1H,d,J=15.4Hz) f 4. 37 (1H, d, J=3. 8Hz), 6. 65 (2H, df J=8. 7Hz) r 6. 72 (1H, d, J=7. 8Hz), 6. 83 (2Hr d, J=8. 5Hz), 7.12 (1H, tr J=8. OHz), 7.40-7.42 (3Hf m), 7. 54 (2Hf d, J= 8.3Hz),8.36(1H, tr J=5.7Hz) 7 NMR1 : 2. 30 (3H, s), 2. 41 (3H, s), 4.13 (1Hf d, J=t5. 6Hz), 4. 23 (2H, d, J=5. 9 Hz), 4. 29 (1H, d, J=15. 6Hz) f 6. 74 (1H, dr J=7.2Hz), 7.11 (1H, t, J=8. OHz), 7. 20 (1H,d, J=7.8Hz), 7· 35 (1H, t, J=7. 7Hz), 7. 39-7.40 (3H,m), 7· 54 (2H, d,J=8· 4Hz), 7· 75 (1H,s), 7. 78 (1H,d, J=7.8Hz), 8· 49 (1H,t, J=5· 9Hz), 12 .93(1H, brs) 9 NMR1:2. 30 (1H, s), 4. 23-4· 31 (4H, m), 6. 82 (2H,d, J=7. 8Hz),7· 14 (1H, t, J =8. OHz), 7. 22 (1H, d, J=7. 7Hz), 7.36 (1H, t, J=7. 6Hz), 7.44 (1H, d, J=7. 8H z),7. 67 (4H, brs),7. 75 (1H, s),7· 79 (1H, d,J=7. 8Hz),8. 51 (1H, t,J=5· 9H z),12.94(1H,brs) 16 NMR1:2.31 (3H, s), 2. 42 (3H, s), 4.11 -4.15 (3H, m), 4. 29 (1H, d, J=15. 6Hz) ,4. 61 (2H,s),6.55 (1H,d,J=7· 6Hz),6. 68 (1H, s), 6· 72-6· 75 (2H,iti),7.11 -7.15 (2H,m), 7.4-7· 44 (3H, in),7, 55 (2H,d,J=8. 2Hz),8.4 (1H,t, J=5_ 9Hz ),12. 97(1H,brs) -117- 200817319 【表5 4】 Ex Dat 20 NMR1: 2· 30 (3H,s),2· 42 (3H,s),3· 37 (3H,s),4· 14 (1H,d,5· 6Hz),4.25 (2H, tf J=5. 7Hz), 4.32 (1H, d, J=15.6Hz), 6. 75 (1H, d, J=7.2Hz) ,7.11 (2H, d,J=8. 3Hz), 7· 16 (1H, d, J=8.1 Hz), 7.42 (2H,d,J=8· 3Hz), 7.46 (1H, d, J=7 • 2Hz),7. 55 (2H,d,J=8.3Hz),7.81 (2H,d,J=8· 3Hz),8_ 52 (1H,t,J=6· 0Hz) ,12.07(1H,brs) 21 NMR1 : 2. 29 (3H, s), 4. 24 (2H, df J=5. 6Hz), 4. 30 (2Hr df J=6. 8Hz), 6.83 (1H, d, J=8. OHz), 7.14 (1H, t, J=8. OHz), 7.19-7. 29 (1H, m), 7. 37 (1H, t, J=8. OH z),7.46 (1H,d, J=8. OHz), 7. 70-7. 90 (4H, m), 8.03-8.15 (2H,m),8· 46-8. 5 8(1H, m),12.94 (1H, brs) 22 NMR1 : 2. 29 (3Hr s) f 4. 23 (2H, d, J=5. 6Hz), 4.30 (2H, dr J=4. OHz), 6. 84 (1H, d, J=8. OHz), 7.15 (1H, t, J=8. OHz), 7. 22 (1H, dr J=7. 6Hz), 7. 36 (1 Wt t, J=8 .OHz) r 7.46 (1H, d, J=8. OHz), 7. 71-7. 82 (2H, m) r 7.88 (2H, d, J=8.4Hz), 7. 98 (2H, d, J=8. 4Hz), 8.47-8.58 (1H, m) 24 _R1:2.30 (3H, s), 2.42 (3H, s),3_ 83 (3H, s), 4.09-4. 35 (4H, m), 6· 73 (1 Hr d, J=8. OHz), 7.1 (2H, d, J=8. OHz), 7.15 (1H, tr J=8.2Hz), 7.41-7.46 (3H, m ),7.55 (2H, d, J=8. OHz), 7. 81 (2H, d, J=8. OHz),8:53 (1H, t, J=5· 9Hz) 26 NMRU2· 31 (3H,s), 2. 42 (3H,s),4· 11-4.33 (4H,m),6· 53 (1H,t,J=2. OHz), 6· 75 (1H,d, J=7. 8Hz), 7.11 (2H,d, J=8· 5Hz), 7.16 (1H,d, J=8. OHz), 7· 41 -7.46 (3H, m), 7. 56 (2H, d, J=8. 2Hz) , 7. 68-7. 72 (3H, m), 8.44-8.46 (2H, m) 28 NMR1 : 2. 30 (3H, s), 2. 42 (3H, s) r 3. 33 (3H, s), 4.15 (1H, df J=15. 8Hz), 4. 25 (2H, d, J=5.8Hz), 4.32 (1H, d, J=15. 7Hz), 6. 64 (1H, d, J=8. OHz), 6.76 (1H, dr J=8. OHz), 6.95 (1H, s), 7.14(1 H, t, J=8. OHz), 7.41-7.47 (4H, m), 7. 55 ( 2H, d, J=8. 2Hz), 8.52 (1H, t, J=6. OHz) r 11.29 (1H, brs) 37 NMR1 : 2.40 (3H, s), 4.14 (1 Hf brs) r 4.25 (2H, d, J=6. OHz), 4.50 (1H, brs), 7 • 22-7· 43 (6H, m),7· 54-7. 68 (3H,m),7· 73-7· 83 (2H,m),8.48-8· 58 (1H,m) ,12.95(1H, brs) 38 NMR1: 2· 39 (3H,s),3· 71 (3H,s), 4· 23 (2H,d,J=6· OHz),4· 32 (2H, s), 7· 05 ( 1H, t,J=8. OHz), 7.11 (1H, dd, J=8. OHz, 2. OHz), 7. 26 (1H, d, J=7. 6Hz),7. 3 2-7.41 (3H, m), 7.46 (1H, dd, J=8. OHz, 2. OHz), 7. 66 (2H, d, J=8.4Hz), 7. 75 (1H, brs), 7. 79 (1H, d, J=8. OHz), 8.45-8.58 (1H, m) J2. 93 (1H, brs) -118- 200817319 【表5 5】 Ex Dat 39 _R1:2. 33 (3H, s),2.41 (3H,s),4.07-4· 35 (4H,m),6· 77 (1H,d,J=7. 6Hz), 7.04 (1H, t, J=8.0Hz), 7.19 (1 Hf d, J=8. OHz), 7.35 (1H, t, J=8. OHz) f 7.40 ( 2H, d, J=8. OHz), 7.53 (2H, d, J=8. OHz),7.58 (1H, d, J=8· OHz), 7· 74 (1H,br s), 7. 78 (1H, d, J=8. OHz), 8.41 -8.56 (1H, m) ,12. 93 (1H, brs) 40 NMR1 :1.16 (3H, t, J=8. OHz). 2.41 (3H, s), 2.82 (2H, d, J=8. OHz), 4.14-4.2 9 (4H,m), 6· 76 (1H,dd,J=8. OHz,0_ 8Hz),7.11 (1H, t,J=8_ OHz),7. 21 (1H,d ,J=8. OHz),7. 33-7.44 (4H,m), 7· 56 (2H,d,J=8. OHz),7· 72-7· 82 (2H,m),8 .46-8.550H,m),12. 93(1H,brs) 42 NMR1 : 1. 21 (3H, t, J=7. 6Hz), 2. 28 (3H, s) r 2. 71 (2H, q, J=7. 6Hz), 4. 07-4.3 5 (4H, m), 6. 75 (1H, df J=8. OHz) f 7.11 (1H, t, J=8. OHz), 7.19 (1Hr df J=8. OH z),7· 35 (1H, t, J=8. OHz),7· 39-7.47 (3H, m), 7· 56 (2H, d,J=8. OHz),7. 74 ( 1H,brs), 7. 78 (1H, d, J=8· OHz),8· 44-8. 55 (1H, m),12· 93 (1H, brs) 49 NMR1 : 2. 30 (3H, s), 2.41 (3H, s), 4.11 (1H, d, J=15. 9Hz), 4. 26 (1H, d, J=15. 9Hz), 4. 32 (2H, d, J=5. 8Hz), 6. 75 (1H, d, J=7.1 Hz), 7.10 (1H, t, J=7. 9Hz), 7· 17 (1H, d, J=1. OHz), 7. 38-7· 42 (3H,m), 7· 54 (2H,d, J=8. 3Hz),8.05 (1H, d,J=1 · 4Hz),8. 57 (1H,t, J=5. 8Hz),12· 5(H 2· 70 (1H,br) 50 NMR1:2. 30 (3H, s),2· 42 (3H,s),4· 07-4. 37 (4H,m), 6.47 (1H,d, J=16· OHz) ,6· 75 (1H, d,J=8. OHz), 7.01 (1H, d, J=8. OHz),7· 13 (1H, t,J=8· OHz),7. 27 (1H, t,J=8. OHz),7.34-7· 59 (8H,m),8. 39-8. 49 (1H,m), 12.42 (1H,brs) 51 NMR1 : 2. 31 (3H, s), 2. 41 (3H, s), 2. 47 (2Hr t, J=8. OHz), 2. 74 (2H, t, J=8. OH z),4. 05-4. 34 (4H,m), 6. 74 (1H, d,J=8. OHz),6. 78 (1H, d, J=8. OHz), 6. 92 ( 1H, s), 7.05 (1H, d, J=8. OHz) ,7.13 (2H, t, J=8. OHz), 7.36-7.47 (3H, m), 7. 55 (2H, df J=8. OHz), 8. 33-8.43 (1H, m), 12.12 (1 Hf s) 74 NMR1:1.16 (3H, t, J=7.6Hz), 2.41 (3H, s), 2. 84 (2H, q, J=7. 6Hz), 4.11-4. 3 1 (4H, m), 6.47 (1H, d, J=16. OHz), 6. 76 (1H, d, J=8. OHz), 7.02 (1H, d, J=8.0 Hz) ,7.12 (1H, t, J=8. OHz) f 7. 28 (1H, tr J=8. OHz), 7.36-7.46 (4H, m) ,7.51 (1H, d, 6. OHz),7· 52 (1H, d, J=8. OHz),7. 57 (2H, d, J=8· OHz), 8_ 38-8. 5 2(1HFm),12.40(1H, brs) 119- 200817319 【表5 6】 Ex Dat 78 NMR1 : 2.30 (3H, s), 4. 21 (2H? d, J=5. 6Hz), 4.31 (2H, s), 6.46 (1H, d, J=16.0 Hz), 6· 84 (1H, d, J=8. 0Hz), 7· 04 (1H, d, J=8· 0Hz),7.17 (1H, t, J=8.0Hz),7 .29 (1H, t, J=8. OHz), 7. 38 (1H, s), 7.43-7.57 (3H,m),7. 89 (2H, d, J=8.4Hz ),7· 99 (2H, d,J=8· 4Hz),8.44 - 8· 50 (1H,m) 79 NMR1:2.31 (3H,s), 4· 17-4.35 (4H, m), 6.46 (1H,d, J=16· OHz), 6.82 (1H,d, J=8. OHz), 7.03 (1Hr d, J=8. OHz), 7.16 (1H, t, J=8. OHz), 7. 28 (1H, t, J=8.0 Hz), 7.38 (1H, s) f 7.43-7.56 (3H, m), 7.68 (4H, s), 8.41-8. 51 (1H, m) 82 NMR1 : 2.32 (3H, s) f 2.47 (2H, t, J=8. OHz), 2. 74 (2H, t, J=8. OHz) r 4.15 (2H, d, J=5. 6Hz) f 4. 24-4. 36 (2H, m), 6. 77-6.87 (2H, m), 6. 93 (1 Hf s), 7.06 (1H, d, J=8. OHz), 7.11-7. 21 (2H, m), 7.47 (2H, d, J=8. OHz) r 7. 90 (2Hr dr J=8. OH z), 7. 99 (2H, df J=8. OHz), 8.36-8.45 (1H, m), 12.12 (1H, s) 85 NMR1 : 2. 25 (3H, s), 2.40 (3H, s), 4.17-4.44 (4H, m), 7.05 (1 Hf d, J=8. OHz), 7.11-7.18 (2H, m), 7. 23 (1H, d, J=8. OHz), 7. 31 (1H, dr J=12. OHz), 7. 36 (1H ,t, J=8. OHz), 7.42 (1H, d, J=8. OHz),7.49 (1H,t, J=8. OHz), 7. 74 (1H, brs) ,7· 75 (1H, s), 7. 79 (1H, d, J=8. OHz),8.46-8_ 55 (1H, m),12.93 (1H,brs) 114 NMR1:2. 29 (3H, s), 2· 41 (3H, s),4.16-4· 34 (4H,m),6. 77 (1H, d, J=7. 6Hz) r 7.12 (1H, t, J=8. OHz), 7. 39-7.42 (3H, m), 7. 53 (2H, d,J=8.4Hz), 8. 63 (1H, s)f8. 67(1H,tf J=6. OHz) 116 _R1:2. 29 (3H, s), 2. 45 (3H, s), 4.09-4· 29 (4H,m), 6. 77 (1H,d, J=8· OHz), 7.12 (1H, t, J=7. 6Hz) , 7.31 (1H, s), 7. 34-7. 49 (3H, m), 7. 50 (1H, s), 7. 56 ( 2H,d,J=7. 6Hz), 8. 42 (1H, t, J=6, OHz) 119 _R1:1.44 (3H, d, J=6. 8Hz), 2. 31 (3H,s), 2. 42 (3H,s), 4.10-4. 30 (4H, m), 4. 65-4. 67 (IH, m), 6. 51 (1H, d, J=7. 6Hz), 6. 61-6. 67 (2Hf m), 6. 74 (1H, d, J =8. OHz), 7.08-7.15 (2Hf m), 7. 39-7.44 (3H, m) r 7.55 (2Hf d, J=8. OHz), 8.3 8(1H,t, J=5.2Hz) 120 NMR1 : 1.45 (3H, d, J=6.8Hz) r 2.31 (3H, s) f 2. 42 (3H, s), 4.11-4. 30 (4H, m), 4. 66-4. 68 (1H, m), 6. 52 (1H, d, J=7. 2Hz), 6. 61-6. 68 (2H, m), 6. 75 (1H, df J =8. OHz), 7. 08-7.15 (2H, m), 7.39-7.44 (3H, m), 7.55 (1H, d, J=8. OHz), 8.3 8(1H,t,J=5.6Hz) -120- 200817319 產業上之利用可行性 本發明之磺胺化合物或其製藥學上容許之鹽具有強力 之EP1受體拮抗作用,因此做爲治療EP1受體相關之疾病 ,特別是下部尿道症狀之藥劑甚爲有用。 序列表Free Text 下列序列表之數字標題< 223 >中,記載以人造序列 之說明。具體言之,序列表中之序列號碼1之序列所示胺 基酸序列乃人工合成之信號肽序列。又,序列表中之序列 號碼2所示胺基酸序列乃人工合成之FLAG序列。 序列表 AP-TWO7015.ST25.txt -121 -
Claims (1)
- 200817319 十、申請專利範圍 1 · 一種含有式(I)所示磺胺化合物或其製藥學上容 許之鹽爲有效成份之EP 1受體拮抗劑, 【化1 9】 R1[式中符號之意義如下所示: A環:苯環、環烷環、或芳香族雜環、 L 1 :單鍵結合、或低級伸烷基、 L2 :低級伸烷基、 R1〜R4 :可爲相同或不同構造,示RG、鹵素、鹵化低級烷 基、-ORG、-0-鹵化低級烷基、-S(0)n-低級烷基、-CN、 -N〇2、含氮雜環基、環烷基、-NH-C0-低級烷基、-NH-CO-NCRMh、-NH-C0-含氮雜環基、-C02R°、-CON(R〇)2 、-CO-低級烷基、-低級伸烷基-ΟΜ、-低級伸烷基-C02Rq ,亦可被取代之芳基,亦可被取代之雜芳基,-〇-亦可被 取代之芳基,-〇-苯甲基,或亦可被取代之雜芳基’ 或R1及R2,以及R3及R4係分別互相在苯環及A環的鄰 接之碳原子上時,可和其所結合之環原子成爲一體’形成 爲5〜7節環烯環、苯環或以選擇自下列G1群中之基所取代 之雜環, -122- 200817319 G1群:低級烷基、氧代基、-OR*5、-低級伸烷基-OR0 ,及-C 0 ·低級院基、 :氫原子或低級烷基、 rqq :氫原子、或可爲-ORG取代之低級烷基、 η : 0、1 或 2、 RA : R〇、 rB : R〇 、 RB : R0,-低級伸烷基-亦可被取代之芳基,-低級伸烷 基-亦可被取代之雜芳基,-低級伸烷基-〇-亦可被取代之芳 基,或-低級伸烷基-〇-亦可被取代之雜芳基, 或RA及RB,分別和其所結合之氮原子成爲一體而形成 含氮雜環]。 2. 如申請專利範圍第1項之EP 1受體拮抗劑,其中, RA示氫原子,RB示-低級伸烷基-亦可被取代之芳基低 級伸烷基-亦可被取代之雜芳基,-低級伸烷基-〇-亦可被取 代之芳基,或-低級伸烷基-〇-亦可被取代之雜芳基。 3. —種式(II)所示磺胺化合物或其製藥學上容許之 【化2 0】-123- 200817319 [式中符號之意義如下所示: A環:苯環、環烷環或芳香族雜環, L 1 :單鍵結合、或低級伸烷基, L2 :低級伸烷基, R1〜R4 :可爲相同或不同構造,示RG、鹵素、鹵化低級烷 基、-OR0、-0·鹵化低級烷基、-S(0)n-低級烷基、-CN、 -N02、含氮雜環基、環烷基、-NH-CO-低級烷基、 -NH-CO-N(Rgg)2、-NH-CO-含氮雜環基、-C02R〇、 -CON(Rg)2、-CO-低級烷基、-低級伸烷基-OR。、-低級伸 烷基-CC^M,亦可被取代之芳基、亦可被取代之雜芳基 、-0·亦可被取代之芳基,-〇-苯甲基,或-0-亦可被取代基 之雜芳基, 或R1及R2,以及R3及R4,分別互相在苯環及A環之鄰 接之碳原子上時,可和其所結合之環原子成爲一體,形成 爲5〜7節環烯環、苯環、或以選擇自下列G1群中之基所取 代之雜環, G1群:低級烷基、氧代基、-0RG、-低級伸院基-〇R() 、及-CO-低級烷基, :氫原子、或低級院基, R00 :氫原子、或可被_org所取代之低級院基’ η : 〇、1 或 2, L3 :低級伸烷基, X :單鍵結合、或-〇-, Β環:苯環、或芳香族雜環, -124- 200817319 R5及R6 :可爲相同或不同構造’示RQ、鹵素、鹵化低 級院基、-〇 R G、-0 -鹵化低級院基、 c N、或_ n 〇 2, Y :單鍵結合、低級伸烷基、低級伸烯基、或-〇_低級 伸烷基, Z : -C02H或其生物學上之等效物、-C〇Nr7r8、或可 爲選擇自上列G 1群之基所取代之含氮雜環基, R7及R8:可爲相同或不同構造,示氫原子、或可爲選 擇自下述G2群中之基所取代之低級烷基, G2群:-OR0、-N(RG)2、-CO2R0及含氮雜環基, 惟不包括4 一( { [N - [ ( 4 一氟苯基)磺醯基]一 N —( 2—甲氧基苯基)甘胺醯基]胺基}甲基)苯甲酸甲醋及N2 —[(4 —氯苯基)磺醯基]—N2— (2,5 -二氟苯基)—N 一 [4 一( 1,2,3 —噻二唑一 4一基)苯甲基]一 d〜丙胺醯胺] 〇 4 ·如申請專利範圍第3項之化合物或其製藥學上容許 之鹽,其中,L1示單鍵結合。 5 ·如申請專利範圍第4項之化合物或其製藥學上容許 之鹽,其中,A環爲苯環。 6 ·如申請專利範圍第5項之化合物或其製藥學上容許 之鹽,其中,X示單鍵結合。 7 ·如申請專利範圍第6項之化合物或其製藥學上容許 之鹽’其中,L2及L3皆示亞甲基。 8 ·如申請專利範圍第7項之化合物或其製藥學上容許 之鹽’其中,2;示_c〇2H或其生物學上之等效物。 -125- 200817319 9. 一種下列式(U_A )所示磺胺化合物或其製藥學 上容許之鹽, 【化2 1】[式中符號之意義如下所示: R1G〜Rl2 :可爲相同或不同構造,示鹵素、低級烷基、鹵 化低級院基、-〇 RG、_ Ο -鹵化低級院基、或-c N, R13 : RG、鹵素、鹵化低級烷基、-ORG、-〇_鹵化低級院基 、或-CN, B環:苯環、或芳香族雜環, R14 : R0、鹵素、或-OR0, V :氫原子、或低級烷基, Y1 :單鍵結合、低級伸烷基、低級伸烯基、或_〇_低級伸 烷基, Z1 : -C02H或其生物學上之等效物]。 1 0 ·如申請專利範圍第3項之化合物或其製藥學上容 許之鹽,其爲選擇自下列群中之化合物: 4-[({1(3-氯-2-甲苯基)-.[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基] -126- 200817319 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲苯基)-N-[(4-氯苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3- [({ N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基 ]甘胺醯基}胺基)甲基]苯氧基乙酸、 4- [({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]-N-(甲磺醯基)苯甲醯胺、 3-[({N-(3-氯-2 -甲苯基)-N-[(4-氰基苯基)磺醯 基]甘胺醯基}胺基)甲基]苯甲酸、 3- {[(化(3-氯-2-甲苯基)->1-[(4-三氟甲基)苯基] 磺醯基}甘胺醯基)胺基]甲基}苯甲酸、 4- [({N-(3-氯-2-甲苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]-2-甲氧基-N-(甲磺醯基)苯甲醯 胺、 3-[({N-(2,3-二氯苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-甲氧基苯基)-N_[(4-甲苯基)磺 醯基]甘胺醯基}胺基)甲基]苯甲酸、 3-[ ( {N- ( 3-溴-2-甲苯基)-N-[ ( 4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[ ( {N- ( 3 -氯-2-甲苯基)-N-[ ( 4 -乙苯基)礦釀基] 甘胺醯基}胺基)甲基]苯甲酸、 3-[({N-(3-氯-2-乙苯基)-N-[(4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]苯甲酸、 -127- 200817319 3-[ ( {N- ( 3-氯-2-甲苯基)-N-[ ( 4-甲苯基)磺醯基] 甘胺醯基}胺基)甲基]肉桂酸、 3-{3-[({N-(3-氯-2-甲苯基)-n_[(4-甲苯基)磺醯 基]甘胺醯基}胺基)甲基]苯基}丙酸、 5-[({N-(3-氯-2-甲苯基)·Ν_[(4_甲苯基)磺醯基] 甘胺醯基}胺基)甲基]噻吩-3-竣酸、 3-[ ( {N- ( 3-氯-2-乙苯基)_Ν·[ ( 甲苯基)磺醯基] 甘胺醯基}胺基)甲基]肉桂酸、 3-{[(Ν-(3·氯-2·甲苯基)-Ν_{[4_(三氟甲基)苯基 ]磺醯基}甘胺醯基)胺基]甲基}肉桂酸、 3-[({Ν-(3-氯-2-甲苯基)氯苯基)磺醯基] 甘胺釀基}胺基)甲基]肉桂酸、 3-(3_{[(Ν-(3-氯-2·甲苯基)·Ν·{[4-(三氟甲基) 苯基]磺醯基}甘胺醯基)胺基]甲基}苯基)丙酸、 3- [ ( {Ν- ( 3-氯-2-甲苯基)-Ν-[ ( 2_氟-4-甲苯基)磺 醯基]甘胺醯基}胺基)甲基]苯甲酸、 2-[({.(3-氯-2_甲苯基)_>^_[(4_甲苯基)磺醯基] 甘胺釀基}胺基)甲基]-1,3 -U惡哇-4-殘酸、 4- [({N-(3-氯-2-甲苯基)-N_[(4_甲苯基)磺醯基] 甘胺醯基}胺基)甲基]噻吩-2-羧酸、 (2S) -2-{3-[({N-(3-氯-2 -甲苯基)-N-[(4 -甲苯 基)磺醯基]甘胺醢基}胺基)甲基]苯氧基丨丙酸,以及 (2R) -2-{3-[ ( {N· ( 3-氯·2 -甲苯基)·ν·[ ( 4 -甲苯 基)磺醯基]甘胺醯基}胺基)甲基]苯氧基}丙酸。 -128- 200817319 1 1. 一種醫藥組成物,其特徵爲含有如申請專利範圍 第3項之化合物或其製藥學上容許之鹽做爲有效成份者。 1 2.如申請專利範圍第1 1項之醫藥組成物’其爲屬於 EP1受體拮抗劑者。 1 3 .如申請專利範圍第1 1項之醫藥組成物’其爲屬於 下部尿道症狀之治療劑者。 1 4.如申請專利範圍第1 3項之醫藥組成物’其中該造 成下部尿道症狀之疾病係過動膀胱、前立腺肥大症、膀胱 頸部硬化症、膀胱炎、或前立腺炎。 1 5 . —種如申請專利範圍第3項之化合物或其製藥學 上容許之鹽之用途,其特徵爲製造下部尿道症狀之治療劑 使用者。 16.如申請專利範圍第15項之用途,其中,導致下部 尿道症狀之疾病係過動膀胱、前立腺肥大症、膀胱頸部硬 化症、膀胱炎、或前立腺炎。 1 7. —種下部尿道症狀之治療方法,其特徵爲包括投 予治療有效量之如申請專利範圍第3項之化合物或其製藥 學上容許之鹽於病患者。 18.如申請專利範圍第17項之治療方法,其中,導 致下部尿道症狀之疾病係爲過動膀胱、前立腺肥大症、膀 胱頸部硬化症、膀胱炎、或前立腺炎。 -129- 200817319 序列表 AP-TW07015.ST25.txt <110> Astellas Pharm Inc. <120> Sulfonamide compound or a salt thereof <130〉 A07015 <150〉 JP2006-218923 O51> 2006-08-10 <160> 2 <170> Patent In version 3.1 <210〉 1 <211〉 16 <212〉 PRT <213> Rattus rattus <220〉 <221> PEPTIDE <222〉(1)·. (16) <223> Inventor; Kubota, Hideki; Toda, Susumu; Tsukamoto, Issei; Fukuda, Yuta; Wakayama, Ryutaro; 0no, Kazuki; Watanabe, Toru; Azami, Hidenori <400〉 1 Met Lys Thr lie lie Ala Leu Ser Tyr lie Phe Cys Leu Val Phe Ala 15 10 15 <210〉 2 <211〉 8 <212〉 PRT <213〉 Artificial <220> <223> Discript ion of artficaial sequence:Flag sequence <400> 2 200817319 七、指定代表圖·· (一) 、本案指定代表圖為:無 (二) 、本代表圖之元件代表符號簡單說明:無 八、本案若有化學式時,請揭示最能顯示發明特徵的化學 式:式[I] 【化1 9】-4-
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006218923 | 2006-08-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW200817319A true TW200817319A (en) | 2008-04-16 |
Family
ID=39033073
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW096129052A TW200817319A (en) | 2006-08-10 | 2007-08-07 | Sulfonamide compound or salt thereof |
Country Status (18)
Country | Link |
---|---|
US (1) | US7973078B2 (zh) |
EP (1) | EP2050446B1 (zh) |
JP (1) | JP5029970B2 (zh) |
KR (1) | KR101352217B1 (zh) |
CN (1) | CN101500554B (zh) |
AU (1) | AU2007282465C1 (zh) |
BR (1) | BRPI0716491A2 (zh) |
CA (1) | CA2660424C (zh) |
ES (1) | ES2467097T3 (zh) |
IL (1) | IL196656A (zh) |
MX (1) | MX2009001512A (zh) |
NO (1) | NO20091058L (zh) |
PL (1) | PL2050446T3 (zh) |
PT (1) | PT2050446E (zh) |
RU (1) | RU2425029C2 (zh) |
TW (1) | TW200817319A (zh) |
WO (1) | WO2008018544A1 (zh) |
ZA (1) | ZA200900549B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0807942A2 (pt) | 2007-02-16 | 2014-07-01 | Ono Pharmaceutical Co | Agente terapêutico para distúrbio de excreção urinária |
US9403789B2 (en) | 2008-02-21 | 2016-08-02 | Sequoia Pharmaceuticals, Inc. | Benzofuran-containing amino acid inhibitors of cytochrome P450 |
US20130109672A1 (en) * | 2010-04-29 | 2013-05-02 | The United States Of America,As Represented By The Secretary, Department Of Health And Human Service | Activators of human pyruvate kinase |
NZ631419A (en) * | 2012-02-29 | 2017-03-31 | Baruch S Blumberg Inst | Inhibitors of hepatitis b virus covalently closed circular dna formation and their method of use |
CA2885908A1 (en) | 2012-09-27 | 2014-04-03 | F. Hoffmann-La Roche Ag | Substituted sulfonamide compounds |
RU2015119635A (ru) * | 2012-10-26 | 2016-12-20 | Мерк Шарп И Доум Корп. | Соединения бензоксазолинона с избирательной активностью в потенциал-зависимых натриевых каналах |
EP2774919A1 (en) * | 2013-03-06 | 2014-09-10 | Pharmeste S.R.L. In Liquidazione | Novel sulfonamide TRPA1 receptor antagonists |
CN109843855B (zh) * | 2016-11-08 | 2021-06-25 | 正大天晴药业集团股份有限公司 | 作为cccDNA抑制剂的磺酰胺类化合物 |
WO2020199683A1 (zh) * | 2019-04-04 | 2020-10-08 | 上海海雁医药科技有限公司 | 氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途 |
CN110698420B (zh) * | 2019-10-25 | 2022-10-14 | 上海阿拉丁生化科技股份有限公司 | 一种2-噁唑甲胺杂环化合物的制备方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2250143A1 (en) | 1996-04-03 | 1997-10-09 | Jeffrey Bergman | Inhibitors of farnesyl-protein transferase |
TW523506B (en) | 1996-12-18 | 2003-03-11 | Ono Pharmaceutical Co | Sulfonamide or carbamide derivatives and drugs containing the same as active ingredients |
ZA984040B (en) * | 1997-05-15 | 1998-11-20 | Ono Pharmaceutical Co | Benzenesulfonamide compounds |
US6211197B1 (en) * | 1998-10-07 | 2001-04-03 | Merck Frosst Canada & Co. | Prostaglandin receptor ligands |
CA2348267A1 (en) | 1998-10-29 | 2000-05-11 | Henry H. Gu | Novel inhibitors of impdh enzyme |
EP1159263A1 (en) | 1999-02-26 | 2001-12-05 | Merck & Co., Inc. | Novel sulfonamide compounds and uses thereof |
WO2000069465A1 (fr) | 1999-05-12 | 2000-11-23 | Ono Pharmaceutical Co., Ltd. | Agents anticancereux contenant des antagonistes de ep1 en tant que principe actif |
JP2003503479A (ja) | 1999-07-06 | 2003-01-28 | バーテックス ファーマシューティカルズ インコーポレイテッド | N置換化グリシン誘導体 |
SK287075B6 (sk) | 1999-08-13 | 2009-11-05 | Biogen Idec Ma Inc. | Inhibítory bunkovej adhézie a farmaceutické prostriedky, ktoré ich obsahujú |
AU2001288623A1 (en) | 2000-09-05 | 2002-03-22 | Tularik, Inc. | Fxr modulators |
WO2002032864A1 (en) | 2000-10-17 | 2002-04-25 | Applied Research Systems Ars Holding N.V. | Pharmaceutically active sulfanilide derivatives |
ATE522513T1 (de) * | 2001-03-12 | 2011-09-15 | Ono Pharmaceutical Co | N-phenylarylsulfonamidverbindung, arzneimittel das diese verbindung als wirkstoff enthält, zwischenprodukt für die verbindung und verfahren zu dessen herstellung |
SE0100873D0 (sv) * | 2001-03-13 | 2001-03-13 | Astrazeneca Ab | Method of treatment |
WO2002072145A1 (fr) * | 2001-03-14 | 2002-09-19 | Ono Pharmaceutical Co., Ltd. | Remedes antidepresseurs contenant un antagoniste ep1 en tant que principe actif |
EP1447096A1 (en) | 2001-11-19 | 2004-08-18 | Ono Pharmaceutical Co., Ltd. | Remedies for urinary frequency |
EP1554239B1 (en) | 2002-10-11 | 2011-01-26 | Actelion Pharmaceuticals Ltd. | Sulfonylamino-acetic acid derivatives and their use as orexin receptor antagonists |
US20050020646A1 (en) | 2003-06-25 | 2005-01-27 | Pfizer Inc. | Treatment of BPH |
JPWO2005000356A1 (ja) | 2003-06-27 | 2006-08-03 | 小野薬品工業株式会社 | 尿路疾患治療剤 |
JP2005206492A (ja) | 2004-01-21 | 2005-08-04 | Sankyo Co Ltd | スルホンアミド化合物 |
US7504431B2 (en) | 2004-04-16 | 2009-03-17 | Bristol-Myers Squibb Company | Sulfonyl amide inhibitors of calcium channel function |
DE102005013967A1 (de) | 2004-11-05 | 2006-10-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Bradykinin-B1-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
-
2007
- 2007-08-07 TW TW096129052A patent/TW200817319A/zh unknown
- 2007-08-09 EP EP07792264.9A patent/EP2050446B1/en active Active
- 2007-08-09 BR BRPI0716491-2A2A patent/BRPI0716491A2/pt not_active IP Right Cessation
- 2007-08-09 MX MX2009001512A patent/MX2009001512A/es active IP Right Grant
- 2007-08-09 ZA ZA200900549A patent/ZA200900549B/xx unknown
- 2007-08-09 KR KR1020087031380A patent/KR101352217B1/ko not_active IP Right Cessation
- 2007-08-09 US US12/297,445 patent/US7973078B2/en not_active Expired - Fee Related
- 2007-08-09 CN CN2007800297302A patent/CN101500554B/zh not_active Expired - Fee Related
- 2007-08-09 RU RU2009108275/04A patent/RU2425029C2/ru not_active IP Right Cessation
- 2007-08-09 CA CA2660424A patent/CA2660424C/en not_active Expired - Fee Related
- 2007-08-09 JP JP2008528874A patent/JP5029970B2/ja not_active Expired - Fee Related
- 2007-08-09 WO PCT/JP2007/065613 patent/WO2008018544A1/ja active Application Filing
- 2007-08-09 PT PT77922649T patent/PT2050446E/pt unknown
- 2007-08-09 AU AU2007282465A patent/AU2007282465C1/en not_active Ceased
- 2007-08-09 PL PL07792264T patent/PL2050446T3/pl unknown
- 2007-08-09 ES ES07792264.9T patent/ES2467097T3/es active Active
-
2009
- 2009-01-22 IL IL196656A patent/IL196656A/en not_active IP Right Cessation
- 2009-03-09 NO NO20091058A patent/NO20091058L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
WO2008018544A1 (fr) | 2008-02-14 |
PL2050446T3 (pl) | 2014-10-31 |
IL196656A (en) | 2013-11-28 |
ES2467097T3 (es) | 2014-06-11 |
CA2660424A1 (en) | 2008-02-14 |
ZA200900549B (en) | 2010-03-31 |
KR20090048401A (ko) | 2009-05-13 |
RU2009108275A (ru) | 2010-09-20 |
KR101352217B1 (ko) | 2014-01-15 |
RU2425029C2 (ru) | 2011-07-27 |
BRPI0716491A2 (pt) | 2014-03-11 |
IL196656A0 (en) | 2009-11-18 |
MX2009001512A (es) | 2009-02-18 |
AU2007282465B2 (en) | 2011-12-01 |
CN101500554B (zh) | 2012-06-27 |
CN101500554A (zh) | 2009-08-05 |
US20090312328A1 (en) | 2009-12-17 |
US7973078B2 (en) | 2011-07-05 |
EP2050446A1 (en) | 2009-04-22 |
JPWO2008018544A1 (ja) | 2010-01-07 |
PT2050446E (pt) | 2014-07-18 |
EP2050446A4 (en) | 2011-02-16 |
AU2007282465C1 (en) | 2012-05-10 |
NO20091058L (no) | 2009-04-24 |
JP5029970B2 (ja) | 2012-09-19 |
EP2050446B1 (en) | 2014-05-07 |
AU2007282465A1 (en) | 2008-02-14 |
CA2660424C (en) | 2014-01-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW200817319A (en) | Sulfonamide compound or salt thereof | |
JP5304785B2 (ja) | スルホンアミド化合物又はその塩 | |
JP5921679B2 (ja) | 血漿カリクレインの阻害薬としてのベンジルアミン誘導体 | |
KR101981347B1 (ko) | 구아니디노벤조산 화합물 | |
KR101046039B1 (ko) | 프로판-1,3-디온 유도체 또는 그의 염 | |
JP2008031064A (ja) | ジアシルピペラジン誘導体 | |
EA021672B1 (ru) | Модуляторы рецепторов сфингозин-1-фосфата и их применение | |
JP2009057282A (ja) | カルボン酸誘導体又はその塩 | |
JP2008063256A (ja) | β‐アミノ酸誘導体 | |
TWI666196B (zh) | 胍基苯甲酸酯化合物 | |
TW200911251A (en) | Tetrahydroisoquinolin-1-one derivatives or salt thereof | |
JP2010532391A (ja) | 置換アミノ−キナゾリノン、前記化合物を含む薬物、それらの使用及び製造方法 | |
JP2022547079A (ja) | てんかんを治療する方法を使用しててんかんを治療する方法 | |
EP2670245B1 (en) | Alpha-ketoheterocycles and methods of making and using | |
KR20080105092A (ko) | 피롤 유도체 또는 그의 염 | |
ES2436608T3 (es) | Composición medicinal para la prevención o el tratamiento de la vejiga hiperactiva asociada a un trastorno nervioso | |
WO2016006593A1 (ja) | 新規ベンズオキサジン誘導体及びこれを含有する医薬 |